WO2024085170A1 - Agent for preventing aftereffects of viral infection - Google Patents
Agent for preventing aftereffects of viral infection Download PDFInfo
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- WO2024085170A1 WO2024085170A1 PCT/JP2023/037639 JP2023037639W WO2024085170A1 WO 2024085170 A1 WO2024085170 A1 WO 2024085170A1 JP 2023037639 W JP2023037639 W JP 2023037639W WO 2024085170 A1 WO2024085170 A1 WO 2024085170A1
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- Prior art keywords
- viral infection
- sequelae
- suppressing
- day
- symptoms
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Definitions
- the present invention relates to an agent for suppressing the aftereffects of viral infection and a composition for suppressing the aftereffects of viral infection that contains the agent as an active ingredient.
- Non-Patent Document 1 some infected people suffer from aftereffects such as fatigue, loss of taste and smell, cough, shortness of breath, and fever even after recovery, resulting in new problems in which they are unable to regain their previous functions.
- Non-Patent Document 2 some people who were previously uninfected experience side effects after vaccination that do not improve, and symptoms continue for several months or more.
- These aftereffects of COVID-19 infection and aftereffects of the vaccine are becoming serious problems as the COVID-19 infection spreads, and the development of treatments for them has become an urgent task.
- no effective treatments or drugs are known.
- the objective of the present invention is to develop and provide a drug that reduces, alleviates, ameliorate, or treats symptoms in patients who develop sequelae of viral infection.
- the inventors conducted extensive research and found that when small doses of clomipramine, a tricyclic antidepressant with a guaranteed safety, were administered to patients with aftereffects of COVID-19 infection and patients with side effects similar to those of COVID-19 after vaccination, both patients showed dramatic improvement in a short period of time, demonstrating remarkable efficacy.
- the present invention is based on this novel finding and provides the following.
- An agent for suppressing sequelae of viral infection comprising a tricyclic compound represented by the following general formula (I) and/or general formula (II) or a salt thereof: [In the formula, R1 represents H or Cl, R2 represents H or a methyl group, and R3 represents H, a methyl group, or any of the functional groups represented by the following formula (III)] (2)
- the agent for suppressing sequelae of viral infection according to (1), wherein the sequelae of viral infection are brain dysfunctions not including psychiatric disorders.
- a composition for suppressing sequelae of viral infection comprising one or more agents for suppressing sequelae of viral infection according to any one of (1) to (5) as an active ingredient.
- the agent for suppressing the aftereffects of viral infection of the present invention can alleviate, reduce, or treat the aftereffects of viral infection with a small dose and without side effects.
- composition for suppressing sequelae of viral infection of the present invention contains one or more agents for suppressing sequelae of viral infection and can be provided in a dosage form that is easy to administer to patients.
- the evaluation value is calculated taking into account gender and age.
- pre indicates the evaluation point at the start of clomipramine administration (initial period), and the results 1 week (1w), 2 weeks (2w), 4 weeks (4w), and 8 weeks (8w) after the start of administration, respectively.
- These are waveform diagrams showing averaged changes in the amount of oxyhemoglobin (oxy-Hb) in the forehead measured by optical topography.
- A shows the waveform diagram of a subject with COVID-19 sequelae in Example 1
- B shows the waveform diagram of a patient with depression
- C shows the waveform diagram of a healthy subject.
- the area between the arrows indicated by a and b is the task enjoyment section, which is the section that best reflects brain activity.
- the first aspect of the present invention is an agent for suppressing sequelae of viral infection.
- the agent for suppressing sequelae of viral infection of the present invention (hereinafter often abbreviated as "the agent") comprises a tricyclic compound having a specific structure or a salt thereof.
- the agent for suppressing sequelae of viral infection of the present invention can reduce, alleviate, ameliorate, or treat sequelae of viral infection.
- viral infection refers, in a narrow sense, to the invasion of a host cell by a virus for proliferation.
- viral infection refers to a viral infection in a broad sense, including vaccination, in addition to the narrow sense of viral infection.
- vaccination refers to the administration of a detoxified, attenuated or non-infectious virus, a part of a viral gene, or a viral protein to a living body in order to promote the production of antibodies against a target virus.
- a detoxified, attenuated or non-infectious virus a part of a viral gene, or a viral protein to a living body in order to promote the production of antibodies against a target virus.
- examples include COVID-19 vaccines, cervical cancer vaccines, and influenza vaccines.
- the virus to be infected with the virus is an animal virus that uses an animal cell as a host.
- the animal virus may be either an RNA virus or a DNA virus.
- it may be any virus belonging to the Coronaviridae, Orthomyxoviridae, Retroviridae, Picornaviridae, Caliciviridae, Astroviridae, Flaviviridae, Togaviridae, Paramyxoviridae, Rhabdoviridae, Filoviridae, Bunyaviridae, Arenaviridae, Reoviridae, or Birnaviridae.
- SARS-CoV-2 SARS coronavirus 2
- Coronaviridae family SARS coronavirus 2
- influenza virus influenza virus of the Orthomyxoviridae family.
- it may be any virus belonging to the Papillomaviridae, Adenoviridae, Herpesviridae, Poxviridae, Iridoviridae, Hepadnaviridae, Circoviridae, Parvoviridae, or Papovaviridae family.
- Specific examples include human papillomavirus of the Papillomaviridae family.
- viral infection refers to a disease or side effect caused by infection with the aforementioned virus.
- Aftereffects of viral infection refers to post-infection symptoms that persist and/or newly appear after a prescribed period of recuperation has elapsed after contracting a viral infection.
- the "prescribed period of recuperation” here refers to the period determined by the government or each local government according to the type of viral infection. For example, in the case of COVID-19, which is classified as a new influenza-like infectious disease (equivalent to Category 2 infectious disease) in Japan, if a positive test is received and symptoms are confirmed, the recuperation period is 10 days, counting from the day of onset as day 0. In addition, if a positive test is received but the patient is asymptomatic, the recuperation period is 7 days, counting from the day of specimen collection as day 0. In addition, in this specification, aftereffects of viral infection refer to symptoms including vaccine aftereffects, unless otherwise specified.
- vaccine sequelae refers to adverse reactions that do not improve after vaccination and persist for a long period of time. As mentioned above, in this specification, vaccine sequelae are considered to be one symptom included in the sequelae of viral infection.
- the symptoms of the aftereffects of viral infection include various symptoms such as physical symptoms, mental symptoms, and cognitive dysfunction caused by brain dysfunction other than mental illness.
- Physical symptoms include, for example, fatigue, tiredness, headache, fever/low-grade fever, dyspnea, taste disorder, smell disorder, insomnia, daytime sleepiness, and stiff shoulders.
- Mental symptoms include, for example, loss of energy, loss of motivation, loss of appetite, loss of interest, irritability, and irritability.
- Cognitive dysfunction includes the decline or loss of concentration, attention, memory including working memory, executive function, language fluency, language memory, and dual tasking.
- brain dysfunction refers to impairment of brain functions such as thinking, emotion, and behavior caused by a disease in the brain.
- “Mental illness” is, in a broad sense, a general term for exogenous, psychogenic, or endogenous functional or organic disorders of the brain.
- mental illness refers to the three disorders classified as schizophrenia, depression, or bipolar disorder in the diagnostic categories of psychopathology.
- “Depression” refers to a type of mood disorder accompanied by symptoms such as low spirits, loss of energy, lack of motivation, loss of interest, loss of appetite, insomnia, sadness, feelings of guilt, self-blame, and suicidal thoughts.
- depression There is no medical definition of depression, and generally, disorders that meet the criteria for a major depressive episode are diagnosed as depression in the operational diagnostic criteria described in the Diagnostic and Statistical Manual of Mental Disorders V (DSM-5) of the American Psychiatric Association (APA) and the International Classification of Diseases-10 (ICD-10) of the WHO.
- DSM-5 Diagnostic and Statistical Manual of Mental Disorders V
- APA American Psychiatric Association
- ICD-10 International Classification of Diseases-10
- SCID-5 Structured Clinical Interview for DSM-5
- a semi-structured interview guide for making the main diagnoses of DSM-5 the subject is diagnosed with depression.
- depression is defined as a condition that is diagnosed not only based on the results of the operational diagnostic criteria but also based on intrinsic results. Details of the SCID-5 will be described in Example 1.
- NIRS near-infrared spectroscopy
- depression-like symptoms refers to symptoms accompanied by brain dysfunction that are partially similar to symptoms of depression, but do not correspond to depression based on the operational diagnostic criteria and intrinsic results.
- the term “healthy individual” refers to a human individual who is in a healthy state.
- the term “healthy state” refers to a state in which at least mental illness and after-effects of viral infection have not developed, and preferably a healthy state without any illness or disorder.
- Tricyclic compound refers to a compound that has three ring structures in its chemical structure. In this specification, unless otherwise specified, it means a tricyclic compound that contains a benzene ring on both sides. Representative examples of such a structure include tricyclic antidepressants.
- the agent for suppressing sequelae of viral infection of the present invention comprises a tricyclic compound represented by the following general formula (I) and/or general formula (II) or a salt thereof.
- R1 represents a hydrogen atom (H) or a chlorine atom (Cl)
- R2 represents H or a methyl group ( -CH3 )
- R3 represents H, -CH3 , or any of the functional groups shown in formula (III) below.
- salt thereof refers to a salt of the tricyclic compound represented by formula (I), which is an acid addition salt of the active compound prepared using an acid. It is preferably a pharma- ceutically acceptable non-toxic acid addition salt.
- acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates, hydrogencarbonates, and perchlorates; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tartrates, malates, citrates, and ascorbates; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, and p-toluenesulfonates; and acidic amino acids such as aspartates and glutamates.
- inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates, hydrogencarbonates, and perchlorates
- organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tartrates, malates, citrates, and ascorbates
- tricyclic compound represented by the general formula (I) include the tricyclic compounds represented by the following formulas (IV) to (X).
- the tricyclic compound represented by formula (IV) is clomipramine
- the tricyclic compound represented by formula (V) is desipramine
- the tricyclic compound represented by formula (VI) is imipramine
- the tricyclic compound represented by formula (VII) is trimipramine
- the tricyclic compound represented by formula (VIII) is lofepramine
- the tricyclic compound represented by formula (IX) is amitriptyline
- the tricyclic compound represented by formula (X) is nortriptyline.
- tricyclic antidepressants are all already approved drugs known as tricyclic antidepressants.
- the aftereffects of viral infection refer to symptoms caused by brain dysfunction that do not include psychiatric disorders such as depression. Therefore, their uses are different from those of conventional tricyclic antidepressants.
- the above tricyclic compounds can be used as inhibitors to reduce, ameliorate, ameliorate, or treat the aftereffects of viral infection.
- composition for suppressing sequelae of viral infection 2-1. Overview
- the second aspect of the present invention is a composition for suppressing sequelae of viral infection (hereinafter often abbreviated as "the composition").
- the composition is characterized in that it contains the agent for suppressing sequelae of viral infection described in the first aspect as an active ingredient.
- the composition for suppressing sequelae of viral infection and the like can be stably provided as a pharmaceutical composition in a form that reduces the burden and invasiveness when administered to a living body and is easier to administer.
- composition for suppressing sequelae of viral infection of the present invention contains an active ingredient as an essential component, and a solvent and/or a carrier as optional components.
- an active ingredient as an essential component
- a solvent and/or a carrier as optional components.
- the present composition contains the agent for suppressing viral infection sequelae described in the first embodiment as an essential active ingredient.
- the present composition may contain one or more different agents for suppressing viral infection sequelae.
- the composition may also contain other active ingredients that have a medicinal effect in suppressing or treating viral infection sequelae or other diseases.
- the amount of the agent for suppressing the sequelae of viral infection contained in the composition varies depending on the type and/or effective amount of the agent, the dosage form of the composition, the type of carrier or additive described below, and the type of disease, and may be determined appropriately taking into account each of the conditions.
- an effective amount refers to the amount necessary for the viral infection sequelae inhibitor to function as an active ingredient in the composition, and which causes little or no harmful side effects in the living body to which it is applied. This effective amount may vary depending on various conditions such as the subject's information, the route of administration, and the number of administrations. Furthermore, it is sufficient that the total amount of active ingredient administered per day (daily dosage unit) reaches an effective amount. Therefore, the composition can be administered multiple times per day, so long as the daily dosage unit of the active ingredient is within a specified range.
- the effective amount of the viral infection sequelae inhibitor contained in the present composition is not limited, but may be, for example, 5 mg to 40 mg, 6 mg to 38 mg, 7 mg to 35 mg, 8 mg to 30 mg, 9 mg to 28 mg, 10 mg to 26 mg, 11 mg to 24 mg, 12 mg to 22 mg, 13 mg to 20 mg, 14 mg to 18 mg, or 15 mg to 16 mg in a daily dosage unit. If the daily dosage for a patient with viral infection sequelae exceeds 40 mg, it may cause new side effects other than viral infection sequelae, which is not preferable.
- the dosage should generally be 50mg-100mg/day (maximum 225mg/day) for clomipramine, which should be orally administered in 1-3 divided doses.
- desipramine should be orally administered at an initial dose of 75mg-150mg/day, gradually increased to a maximum of 300mg/day
- imipramine should be orally administered at an initial dose of 30mg-70mg/day, gradually increased to a maximum of 200mg/day (maximum 300mg/day)
- trimipramine should be orally administered at an initial dose of 50mg-100mg/day, gradually increased to a maximum of 200mg/day (maximum 300mg/day)
- lofepramine should be orally administered at 10mg-25mg/time, 2-3 times a day, gradually increased to a maximum of 300mg/day.
- amitriptyline must be orally administered at an initial dose of 30-75 mg/time, gradually increasing to 150 mg/day, and nortriptyline must be orally administered at 10-25 mg/time, 2-3 times a day, gradually increasing to a maximum of 150 mg/day.
- the viral infection sequelae suppressant contained in the present composition can be effective in a small amount compared to when used as an antidepressant, and therefore the side effects are less and the cost can be reduced.
- the term “subject” refers to a human living body to which the viral infection sequelae inhibitor or the present composition is applied.
- subject information refers to various individual information on the subject to which the composition is applied. For example, this includes the overall health condition, the progression and severity of a disease or illness if present, age, weight, sex, diet, drug sensitivity, the presence or absence of concomitant drugs, and resistance to treatment.
- the effective amount of the inhibitor in the present composition, and the application amount calculated based on this, are ultimately determined by the judgment of a doctor or other professional depending on the information of each individual subject, etc.
- the present composition may contain a pharma- ceutically acceptable solvent.
- the solvent is an optional component of the present composition, and may be added as necessary.
- “Pharmaceutically acceptable” means that the solvent is harmless or has low toxicity to the living body, and can be generally used in the field of formulation technology, preferably in pharmaceutical compositions.
- Solvents include, for example, water or aqueous solutions, and organic solvents.
- Pharmaceutically acceptable aqueous solutions include, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, phosphate buffer, and sodium acetate buffer.
- Adjuvants here include, for example, D-sorbitol, D-mannose, D-mannitol, sodium chloride, and other low-concentration nonionic surfactants, polyoxyethylene sorbitan fatty acid esters, etc.
- Pharmaceutically acceptable organic solvents include, for example, ethanol, butanol, etc.
- composition may contain a pharma- ceutically acceptable carrier, which is an optional component of the composition and may be added as needed.
- Carriers include, for example, excipients, binders, disintegrants, fillers, suspending agents, diluents, solubilizers, dispersants, surfactants, emulsifiers, soothing agents, stabilizers, preservatives, antiseptics, antioxidants, buffers, bulking agents, moisturizing agents (e.g., glycerin, starch, etc.), adsorbents (e.g., starch, lactose, kaolin, bentonite, colloidal silicic acid, etc.), colorants, flavors, sweeteners, and isotonicity agents.
- excipients binders, disintegrants, fillers, suspending agents, diluents, solubilizers, dispersants, surfactants, emulsifiers, soothing agents, stabilizers, preservatives, antiseptics, antioxidants, buffers, bulking agents, moisturizing agents (e.g., glycerin, starch
- Such carriers are primarily used to facilitate the formation of dosage forms and maintain the dosage form and drug efficacy, as well as to make the active ingredient, the agent for suppressing viral infection sequelae, less susceptible to degradation in the body, and may be used appropriately as needed.
- the dosage form of the present composition is not particularly limited as long as it does not inactivate the active ingredient, the viral infection sequelae suppressor, and other active ingredients, and can exert the pharmacological effect of the active ingredient in the living body after administration.
- the specific dosage form of the present composition may be appropriately selected depending on the administration method and/or prescription conditions. In general, the administration method can be roughly divided into oral administration and parenteral administration, and the present composition may be made into a dosage form suitable for each administration method.
- dosage forms include solids (including tablets, pills, sublingual tablets, capsules, and drops), granules, powders, and liquids (including oral solutions, suspensions, emulsions, and syrups).
- Solids can be made into dosage forms with coatings known in the art, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, and multi-layered tablets, if necessary.
- Parenteral administration can be divided into systemic administration and local administration, and local administration can be further divided into intratissue administration, transepidermal administration, transmucosal administration, and transrectal administration.
- the composition may be in a dosage form suitable for each administration method.
- a dosage form suitable for systemic or intratissue administration may be an injection, which is a liquid.
- Dosage forms suitable for transepidermal or transmucosal administration may be liquids (including aerosols, liniments, eye drops, nasal drops, and inhalants), suspensions (including emulsions and creams), powders (including nasal drops and inhalants), pastes, gels, ointments, plasters, etc.
- Dosage forms suitable for rectal administration may be suppositories, etc.
- the method of administration of the present composition can be broadly divided into parenteral administration and oral administration as described above.
- Oral administration is generally systemic administration, but parenteral administration can be further divided into local administration and systemic administration.
- the method of administration of the present composition can be appropriately selected according to symptoms or the degree of progression, and may be either local administration or systemic administration. Since the aftereffects of viral infection are symptoms caused by brain dysfunction other than psychiatric disorders that exhibit depression-like symptoms, the main site of onset is the brain. Therefore, for systemic administration, for example, oral administration or intravascular injection can be adopted. Furthermore, for local administration, intracerebral administration by injection can be adopted.
- the active ingredient, the viral infection aftereffect suppressant needs to pass through the brain barrier and be delivered to the target brain, but as shown in the examples described later, the present composition can also exert its effect by oral administration.
- Oral administration is particularly preferable as a method of administration of the present composition because it is extremely low invasive and easy to administer.
- Example 1 Treatment of COVID-19 sequelae in healthy individuals (1)> (the purpose) The composition for suppressing viral infection sequelae of the present invention was administered to patients who were in a healthy state but had contracted COVID-19 and developed viral infection sequelae, and its efficacy was examined.
- Subject A woman in her 40s with COVID-19.
- Vaccination history Received two doses of the Pfizer COVID-19 vaccine.
- COVID-19 infection and symptoms More than six months after receiving the second dose, she contracted the virus through an infected family member.
- Symptoms included neck pain, generalized pain, headache, fever, and fatigue.
- Progress 10 days after the end of the recuperation period, pain in the neck and shoulders, tension, joint pain, and fatigue persisted. 24 days after testing positive, symptoms such as inability to process information such as dual tasks, decreased concentration, fatigue, and insomnia persisted even after returning to work.
- SCID-5 Structured Clinical Interview for DSM-5
- the SCID-5 is a semi-structured interview guide for determining the major diagnoses of the DSM-5. It is divided into modules A to L for each diagnosis, and allows systematic evaluation of diagnoses such as depression, schizophrenia, and anxiety disorders. To determine each diagnosis, it is necessary to evaluate whether or not the criteria within each module are met. It is usually administered by clinicians who are familiar with the DSM-5 classification and the APA diagnostic criteria.
- NIRS Optical topography test
- NIRS is a brain function mapping method using near-infrared light. It uses near-infrared light to measure changes in cerebral hemoglobin from the scalp, and the results are used to measure cerebral blood volume. Oxyhemoglobin in particular is thought to reflect brain activity, and the relationship between changes in the state of oxyhemoglobin and mental illness has been clarified.
- the Ministry of Health, Labor and Welfare approved "Optical topography-based differential diagnosis aid for depressive symptoms" for patients with schizophrenia (F2) and mood disorder (F3) in the International Classification of Diseases (ICD-10) as advanced medical care, and in 2014 it was covered by insurance.
- the 52-channel ETG-4000 equipment is used (https://www.innervision.co.jp/suite/hitachi/technote/110158/).
- a verbal fluency task is administered as a cognitive task to measure changes in hemoglobin concentration.
- VFT verbal fluency task
- the subject is first asked to repeat "a, i, u, e, o" for 30 seconds, and then for the next 60 seconds, a letter from the entire hiragana alphabet is presented every 20 seconds, and the subject is asked to say as many words beginning with that letter as they can think of.
- the subject is asked to repeat "a, i, u, e, o" again, and cerebral blood volume is measured during this time.
- Figure 1 shows the time course of changes in cognitive function after the start of clomipramine administration
- Figure 2 shows the changes in oxyhemoglobin (oxy-Hb) levels in the forehead measured by optical topography.
- Clomipramine was administered orally at 10 mg per day and the patient's condition was monitored.
- Improved insomnia I was able to fall asleep again after waking up in the middle of the night
- working memory improved to -1.0 ( Figure 1).
- Working memory again declined, but improved to 0.3 by day 28 ( Figure 1).
- [28th day of taking (4 weeks)] We were able to carry out our overcrowded work and still have some spare capacity. It became possible to act efficiently.
- Example 2 Treatment of COVID-19 sequelae in patients with depression (1)> (the purpose)
- the composition for suppressing viral infection sequelae of the present invention was administered to depressed patients who had developed viral infection sequelae after contracting COVID-19, and its efficacy was examined.
- Example 3 Treatment of COVID-19 sequelae in patients with depression (2)> (the purpose)
- the composition for suppressing viral infection sequelae of the present invention was administered to depressed patients who had developed viral infection sequelae after contracting COVID-19, and its efficacy was examined.
- Subject A woman in her 40s with mild depression and panic disorder who was infected with COVID-19.
- Medication history escitalopram 10mg/day, clonazepam 0.25mg/day.
- Vaccination history Received two doses of COVID-19 vaccine.
- COVID-19 infection and symptoms After receiving the second dose of the vaccine, she contracted the virus through a family member who was infected. Her fatigue worsened day by day, along with coughing and fever. After difficulty breathing and insomnia, her oxygen saturation ( SpO2 ) reached 92% and she was hospitalized on the seventh day after onset, and oxygen administration was started immediately after.
- SpO2 her oxygen saturation
- Example 2 She was administered IVH (total parenteral nutrition) from the left neck, and was hospitalized in the ICU for two weeks, followed by two weeks on a general bed. Progression: After being discharged from the hospital, fatigue, difficulty breathing during movement, and chest tightness continued for about three weeks. Although mentally stable, the patient developed olfactory and tasting disorders as the fatigue improved.
- ⁇ Diagnosis result As in Example 2, the subject had been undergoing treatment for depression with antidepressants since before COVID-19 infection and had been in remission for a long time. In addition, at the time of examination after COVID-19 infection, the subject did not meet the criteria for a depressive episode in DSM-5. Therefore, the subject's symptoms were determined to be COVID-19 sequelae rather than a worsening of depressive symptoms.
- -Treatment was started: Clomipramine was administered orally at 10 mg per day and the patient's progress was monitored.
- Example 4 Treatment of vaccine sequelae in patients with depression (the purpose)
- the composition for suppressing viral infection sequelae of the present invention was administered to non-COVID-19 infected depressed patients who developed vaccine sequelae after receiving the COVID-19 vaccine, and its efficacy was examined.
- Example 5 Treatment of COVID-19 sequelae in healthy individuals (2)> (the purpose) The efficacy of the drug was examined in patients of a different age group from that in Example 1 who were in a healthy state but contracted COVID-19 and developed sequelae of viral infection. (Method) Subject: A woman in her 50s with COVID-19.
- Vaccination history Received three doses of the Pfizer COVID-19 vaccine.
- COVID-19 infection and symptoms After receiving the third dose of the vaccine, she contracted the virus at work, where COVID-19 was prevalent. She began coughing, but an antigen test at work was negative. After returning home, she developed a fever of around 38 degrees, and a PCR test the next day determined that she was positive.
- - Acute symptoms fever, cough, shortness of breath, fatigue, headache, loss of taste and smell, oxygen saturation ( SpO2 ) decreased to 88%.
- SpO2 oxygen saturation
- Example 1 It was confirmed using the evaluation method of Example 1 that the symptoms in the subjects of this example were not depressive symptoms.
- (1) Diagnostic results (a) The evaluation of depressive symptoms based on the SCID-5 did not meet the criteria for diagnosing depression, and therefore it was determined that the patient did not have depression. (b) In the cognitive function evaluation, the subjects' cognitive functions before taking clomipramine were converted and calculated into Z-scores (a value between -1.0 and 1.0, taking into account gender and age, with the general average being used). Verbal fluency was the lowest at -1.30, followed by working memory at -0.96. These results revealed that the subjects' verbal fluency had declined significantly compared to the general average for women in their 50s.
- Clomipramine was administered orally at 10 mg per day and the patient's condition was monitored. [13th day of taking the drug (2 weeks)] Although some changes were observed in physical symptoms and cognitive impairment, the dose of clomipramine was increased to 20 mg per day in an attempt to achieve further improvement, and the patient's progress was monitored. [27th day of taking the drug (4 weeks)] On a subjective scale of 100, dyspnea on exertion improved dramatically to 20. Similarly, brain fog, cognitive impairment (speed of processing, ability to concentrate), and executive dysfunction improved to 30. Fatigue also improved to 70. [Day 41 (6 weeks)] Brain fog, cognitive impairment, and executive dysfunction further improved to 10.
- a cognitive assessment was performed, with verbal fluency improving from -1.03 to -0.47, and information processing speed improving from 0.02 to 0.31.
- [56th day of taking the drug (8th week)] Although the above symptoms were improved, the patient still had no clear feeling about fatigue, and the sleep disorder had not improved. Therefore, the dose of clomipramine was increased to 30 mg per day and the progress was observed.
- Example 1 to 6 From the results of each example The results of Examples 1 to 6 are shown in Table 1. In all cases of Examples 1 to 6, despite the extremely low dose of 10 mg/day to 30 mg/day, after administration of clomipramine, digestive symptoms, fatigue, taste disorders, and olfactory disorders were alleviated in a short period of time. Meanwhile, because of the low dose, no side effects were observed. It has been revealed that clomipramine is effective in alleviating, remitigating, and treating viral infection sequelae in patients with viral infection sequelae, regardless of age, sex, and medical history (current medical history) before the onset of viral infection sequelae.
- Clomipramine is a type of tricyclic antidepressant.
- the symptoms of the digestive system, fatigue, taste disorder, olfactory disorder, etc. which developed after COVID-19 infection or after COVID-19 vaccination, were significantly improved by administration of clomipramine.
- All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.
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Abstract
The purpose of the prevent invention is to develop and provide a drug for alleviating, resolving, remitting or treating a symptom of a patient who develops aftereffects of a viral infection. A tricyclic compound represented by general formula (I) and/or general formula (II) or a salt thereof is provided as an agent for preventing aftereffects of a viral infection. [In the formulae, R1 represents H or Cl; R2 represents H or a methyl group; and R3 represents any one of H, a methyl group, and a functional group represented by formula (III).]
Description
本発明はウイルス感染後遺症抑制剤及びそれを有効成分とするウイルス感染後遺症抑制組成物に関する。
The present invention relates to an agent for suppressing the aftereffects of viral infection and a composition for suppressing the aftereffects of viral infection that contains the agent as an active ingredient.
2019年に全世界に感染拡大し、パンデミックを引き起こした新型コロナウイルス感染症（COVID-19）は、その後も様々な変異株の出現等により、未だ終息の兆しが見えない。近年では各国での感染拡大防止策の徹底や、新型コロナウイルスSARS-CoV-2に対するワクチンの開発と接種が進み、感染者の増減を繰り返しながらも拡大は一定の落ち着きを見せている。
The novel coronavirus disease (COVID-19), which spread across the world in 2019 and caused a pandemic, shows no signs of ending due to the emergence of various mutant strains. In recent years, with countries taking strict measures to prevent the spread of infection and progress being made in developing and administering vaccines against the new coronavirus SARS-CoV-2, the spread of the virus has shown signs of calming down to a certain extent, although the number of infected people has fluctuated.
しかし、一方で、感染者の一部では、治癒後も倦怠感、味覚及び嗅覚障害、咳、息苦しさ、発熱等の後遺症を生じ、従来の機能を取り戻せないという新たな問題が発生している（非特許文献１）。また、未感染者であったにもかかわらず、ワクチン接種後の副反応が軽快せず、症状が数か月以上にわたり続く者もいる（非特許文献２）。このような新型コロナウイルス感染後の後遺症やワクチン後遺症は、新型コロナウイルス感染の伝播に伴い深刻な問題と化しており、その治療法の開発が喫緊の課題となっている。しかし、現在までのところ、それらに有効な治療法や治療薬は知られていない。
However, on the other hand, some infected people suffer from aftereffects such as fatigue, loss of taste and smell, cough, shortness of breath, and fever even after recovery, resulting in new problems in which they are unable to regain their previous functions (Non-Patent Document 1). In addition, some people who were previously uninfected experience side effects after vaccination that do not improve, and symptoms continue for several months or more (Non-Patent Document 2). These aftereffects of COVID-19 infection and aftereffects of the vaccine are becoming serious problems as the COVID-19 infection spreads, and the development of treatments for them has become an urgent task. However, to date, no effective treatments or drugs are known.
本発明の課題は、ウイルス感染後遺症を発症する患者の症状を軽減、軽快、寛解、又は治療する薬剤を開発し、それを提供することである。
The objective of the present invention is to develop and provide a drug that reduces, alleviates, ameliorate, or treats symptoms in patients who develop sequelae of viral infection.
上記課題を解決するために、本発明者らは鋭意研究を重ねた結果、COVID-19罹患後の後遺症を有する患者、及びCOVID-19ワクチン接種後のCOVID-19後遺症に類似の副反応を有する患者に対して、安全性が保証されている既承認薬で、三環系抗うつ薬のクロミプラミンを少量投与したところ、いずれの患者も短期間で劇的な改善がみられる等の著効が明らかとなった。本発明は当該新規知見に基づくものであって、以下を提供する。
In order to solve the above problems, the inventors conducted extensive research and found that when small doses of clomipramine, a tricyclic antidepressant with a guaranteed safety, were administered to patients with aftereffects of COVID-19 infection and patients with side effects similar to those of COVID-19 after vaccination, both patients showed dramatic improvement in a short period of time, demonstrating remarkable efficacy. The present invention is based on this novel finding and provides the following.
（１）以下の一般式（I）及び／又は一般式（II）で示される三環式化合物又はその塩からなるウイルス感染後遺症抑制剤。
［式中、R1はH又はClを表し、R2はH又はメチル基を表し、R3はH、メチル基、又は以下の式（III)で示す官能基のいずれかを表す。］
（２）前記ウイルス感染後遺症が精神疾患を含まない脳機能障害である、（１）に記載のウイルス感染後遺症抑制剤。
（３）前記ウイルス感染がワクチン接種を含む、（１）又は（２）に記載のウイルス感染後遺症抑制剤。
（４）前記ワクチン接種に用いるワクチンがCOVID-19ワクチン、インフルエンザワクチン、又は子宮頸癌ワクチンである、（３）に記載のウイルス感染後遺症抑制剤。
（５）ウイルスがSARSコロナウイルス2、インフルエンザウイルス、又はヒトパピローマウイルスである、（１）又は（２）に記載のウイルス感染後遺症抑制剤。
（６）（１）～（５）のいずれかに記載のウイルス感染後遺症抑制剤を有効成分として１又は２以上含むウイルス感染後遺症抑制組成物。
（７）一日の投与単位中に10mg以上40mg以下の前記ウイルス感染後遺症抑制剤を含む、（６）に記載のウイルス感染後遺症抑制組成物。
本明細書は本願の優先権の基礎となる日本国特許出願番号2022-167026号の開示内容を包含する。 (1) An agent for suppressing sequelae of viral infection, comprising a tricyclic compound represented by the following general formula (I) and/or general formula (II) or a salt thereof:
[In the formula, R1 represents H or Cl, R2 represents H or a methyl group, and R3 represents H, a methyl group, or any of the functional groups represented by the following formula (III)]
(2) The agent for suppressing sequelae of viral infection according to (1), wherein the sequelae of viral infection are brain dysfunctions not including psychiatric disorders.
(3) The agent for suppressing sequelae of a viral infection according to (1) or (2), wherein the viral infection includes vaccination.
(4) The agent for suppressing sequelae of a viral infection described in (3), wherein the vaccine used for the vaccination is a COVID-19 vaccine, an influenza vaccine, or a cervical cancer vaccine.
(5) The agent for suppressing sequelae of a viral infection according to (1) or (2), wherein the virus is SARS coronavirus 2, influenza virus, or human papillomavirus.
(6) A composition for suppressing sequelae of viral infection, comprising one or more agents for suppressing sequelae of viral infection according to any one of (1) to (5) as an active ingredient.
(7) A composition for suppressing sequelae of viral infection according to (6), comprising 10 mg or more and 40 mg or less of the agent for suppressing sequelae of viral infection in a daily dosage unit.
This specification includes the disclosure of Japanese Patent Application No. 2022-167026, which is the priority basis of this application.
（３）前記ウイルス感染がワクチン接種を含む、（１）又は（２）に記載のウイルス感染後遺症抑制剤。
（４）前記ワクチン接種に用いるワクチンがCOVID-19ワクチン、インフルエンザワクチン、又は子宮頸癌ワクチンである、（３）に記載のウイルス感染後遺症抑制剤。
（５）ウイルスがSARSコロナウイルス2、インフルエンザウイルス、又はヒトパピローマウイルスである、（１）又は（２）に記載のウイルス感染後遺症抑制剤。
（６）（１）～（５）のいずれかに記載のウイルス感染後遺症抑制剤を有効成分として１又は２以上含むウイルス感染後遺症抑制組成物。
（７）一日の投与単位中に10mg以上40mg以下の前記ウイルス感染後遺症抑制剤を含む、（６）に記載のウイルス感染後遺症抑制組成物。
本明細書は本願の優先権の基礎となる日本国特許出願番号2022-167026号の開示内容を包含する。 (1) An agent for suppressing sequelae of viral infection, comprising a tricyclic compound represented by the following general formula (I) and/or general formula (II) or a salt thereof:
(3) The agent for suppressing sequelae of a viral infection according to (1) or (2), wherein the viral infection includes vaccination.
(4) The agent for suppressing sequelae of a viral infection described in (3), wherein the vaccine used for the vaccination is a COVID-19 vaccine, an influenza vaccine, or a cervical cancer vaccine.
(5) The agent for suppressing sequelae of a viral infection according to (1) or (2), wherein the virus is SARS coronavirus 2, influenza virus, or human papillomavirus.
(6) A composition for suppressing sequelae of viral infection, comprising one or more agents for suppressing sequelae of viral infection according to any one of (1) to (5) as an active ingredient.
(7) A composition for suppressing sequelae of viral infection according to (6), comprising 10 mg or more and 40 mg or less of the agent for suppressing sequelae of viral infection in a daily dosage unit.
This specification includes the disclosure of Japanese Patent Application No. 2022-167026, which is the priority basis of this application.
本発明のウイルス感染後遺症抑制剤によれば、少量の投与で、副作用もなくウイルス感染後遺症を軽快、軽減、又は治療することができる。
The agent for suppressing the aftereffects of viral infection of the present invention can alleviate, reduce, or treat the aftereffects of viral infection with a small dose and without side effects.
本発明のウイルス感染後遺症抑制組成物によれば、1又は2以上のウイルス感染後遺症抑制剤を包含し、患者に投与しやすい剤形で提供することができる。
The composition for suppressing sequelae of viral infection of the present invention contains one or more agents for suppressing sequelae of viral infection and can be provided in a dosage form that is easy to administer to patients.
１．ウイルス感染後遺症抑制剤
１－１．概要
本発明の第1の態様はウイルス感染後遺症抑制剤である。本発明のウイルス感染後遺症抑制剤（本明細書では、以下、しばしば「本抑制剤」と略称する）は所定の構造を有する三環式化合物又はその塩からなる。本発明のウイルス感染後遺症抑制剤によれば、ウイルス感染後遺症を軽減、軽快、寛解、又は治療することができる。 1. Agent for suppressing sequelae of viral infection 1-1. Overview The first aspect of the present invention is an agent for suppressing sequelae of viral infection. The agent for suppressing sequelae of viral infection of the present invention (hereinafter often abbreviated as "the agent") comprises a tricyclic compound having a specific structure or a salt thereof. The agent for suppressing sequelae of viral infection of the present invention can reduce, alleviate, ameliorate, or treat sequelae of viral infection.
１－１．概要
本発明の第1の態様はウイルス感染後遺症抑制剤である。本発明のウイルス感染後遺症抑制剤（本明細書では、以下、しばしば「本抑制剤」と略称する）は所定の構造を有する三環式化合物又はその塩からなる。本発明のウイルス感染後遺症抑制剤によれば、ウイルス感染後遺症を軽減、軽快、寛解、又は治療することができる。 1. Agent for suppressing sequelae of viral infection 1-1. Overview The first aspect of the present invention is an agent for suppressing sequelae of viral infection. The agent for suppressing sequelae of viral infection of the present invention (hereinafter often abbreviated as "the agent") comprises a tricyclic compound having a specific structure or a salt thereof. The agent for suppressing sequelae of viral infection of the present invention can reduce, alleviate, ameliorate, or treat sequelae of viral infection.
１－２．用語の定義とその範囲
本明細書で使用する用語について以下で定義する。
「ウイルス感染」とは、狭義にはウイルスが増殖のために宿主細胞内に侵入することをいう。本明細書においては、前記狭義のウイルス感染に加え、ワクチン接種を包含する広義のウイルス感染を意味する。 1-2. Definition of Terms and Their Scope The terms used in this specification are defined below.
The term "viral infection" refers, in a narrow sense, to the invasion of a host cell by a virus for proliferation. In the present specification, the term "viral infection" refers to a viral infection in a broad sense, including vaccination, in addition to the narrow sense of viral infection.
本明細書で使用する用語について以下で定義する。
「ウイルス感染」とは、狭義にはウイルスが増殖のために宿主細胞内に侵入することをいう。本明細書においては、前記狭義のウイルス感染に加え、ワクチン接種を包含する広義のウイルス感染を意味する。 1-2. Definition of Terms and Their Scope The terms used in this specification are defined below.
The term "viral infection" refers, in a narrow sense, to the invasion of a host cell by a virus for proliferation. In the present specification, the term "viral infection" refers to a viral infection in a broad sense, including vaccination, in addition to the narrow sense of viral infection.
本明細書において「ワクチン接種」とは、標的ウイルスに対する抗体産生を促進するために、無毒化、弱毒化若しくは非感染化されたウイルス、ウイルス遺伝子の一部、又はウイルスタンパク質を生体に投与することをいう。ワクチンの種類は問わない。例えば、COVID-19ワクチン、子宮頸癌ワクチン、インフルエンザワクチン等が挙げられる。
In this specification, "vaccination" refers to the administration of a detoxified, attenuated or non-infectious virus, a part of a viral gene, or a viral protein to a living body in order to promote the production of antibodies against a target virus. There is no restriction on the type of vaccine. Examples include COVID-19 vaccines, cervical cancer vaccines, and influenza vaccines.
本明細書においてウイルス感染の対象となるウイルスは、動物細胞を宿主とする動物ウイルスである。動物ウイルスは、RNAウイルス又はDNAウイルスのいずれであってもよい。例えば、RNAウイルスであれば、コロナウイルス科、オルソミクソウイルス科、レトロウイルス科、ピコルナウイス科、カリシウイルス科、アストロウイスル科、フラビウイスル科、トガウイルス科、パラミクソウイルス科、ラブドウイルス科、フィロウイルス科、ブニヤウイルス科、アレナウイルス科、レオウイルス科又はビルナウイルス科に属するいずれのウイルスであってもよい。具体例として、コロナウイルス科のSARS-CoV-2（SARSコロナウイルス2）、又はオルソミクソウイルス科のインフルエンザウイルスが挙げられる。また、DNAウイルスであれば、パピローマウイルス科、アデノウイルス科、ヘルペスウイルス科、ポックスウイルス科、イリドウイルス科、ヘパドナウイルス科、サーコウイルス科、パルボウイルス科、又はパポバウイルス科に属するいずれのウイルスであってもよい。具体例として、パピローマウイルス科のヒトパピローマウイルスが挙げられる。
In this specification, the virus to be infected with the virus is an animal virus that uses an animal cell as a host. The animal virus may be either an RNA virus or a DNA virus. For example, if it is an RNA virus, it may be any virus belonging to the Coronaviridae, Orthomyxoviridae, Retroviridae, Picornaviridae, Caliciviridae, Astroviridae, Flaviviridae, Togaviridae, Paramyxoviridae, Rhabdoviridae, Filoviridae, Bunyaviridae, Arenaviridae, Reoviridae, or Birnaviridae. Specific examples include SARS-CoV-2 (SARS coronavirus 2) of the Coronaviridae family, or influenza virus of the Orthomyxoviridae family. In addition, if it is a DNA virus, it may be any virus belonging to the Papillomaviridae, Adenoviridae, Herpesviridae, Poxviridae, Iridoviridae, Hepadnaviridae, Circoviridae, Parvoviridae, or Papovaviridae family. Specific examples include human papillomavirus of the Papillomaviridae family.
本明細書において「ウイルス感染症」とは、前記ウイルス感染により発症する疾患又は副反応をいう。
In this specification, "viral infection" refers to a disease or side effect caused by infection with the aforementioned virus.
「ウイルス感染後遺症」とは、ウイルス感染症の罹患後、所定の療養期間経過した後に継続して見られる、及び／又は新たに発生する罹患後症状をいう。ここで言う「所定の療養期間」とは、政府又は各地方自治体がウイルス感染症の種類に応じて定めた期間をいう。例えば、日本国内において新型インフルエンザ等感染症（感染症２類相当）という位置づけ時のCOVID-19であれば、陽性判断を受け、かつ発症が認められた場合、療養期間は発症日を0日目として10日間である。また、陽性判断を受けたが無症状の場合、療養期間は、検体採取日を0日目として7日間である。なお、本明細書におけるウイルス感染後遺症は、特に断りのない限り、ワクチン後遺症を含む症状をいう。
"Aftereffects of viral infection" refers to post-infection symptoms that persist and/or newly appear after a prescribed period of recuperation has elapsed after contracting a viral infection. The "prescribed period of recuperation" here refers to the period determined by the government or each local government according to the type of viral infection. For example, in the case of COVID-19, which is classified as a new influenza-like infectious disease (equivalent to Category 2 infectious disease) in Japan, if a positive test is received and symptoms are confirmed, the recuperation period is 10 days, counting from the day of onset as day 0. In addition, if a positive test is received but the patient is asymptomatic, the recuperation period is 7 days, counting from the day of specimen collection as day 0. In addition, in this specification, aftereffects of viral infection refer to symptoms including vaccine aftereffects, unless otherwise specified.
本明細書において「ワクチン後遺症」とは、ワクチン接種後の副反応が軽快せず、長期にわたって持続する症状をいう。前述の通り、本明細書ではワクチン後遺症をウイルス感染後遺症に包含される一症状とする。
In this specification, "vaccine sequelae" refers to adverse reactions that do not improve after vaccination and persist for a long period of time. As mentioned above, in this specification, vaccine sequelae are considered to be one symptom included in the sequelae of viral infection.
本明細書におけるウイルス感染後遺症の症状は、精神疾患以外の脳機能障害を原因とする身体症状、精神症状、及び認知機能障害等の様々な症状を包含する。身体症状には、例えば、倦怠感、疲労感、頭痛、発熱・微熱、呼吸困難、味覚障害、嗅覚障害、不眠、日中の眠気、肩凝り等が挙げられる。精神症状には、例えば、気力低下、意欲低下、食欲低下、興味低下、易刺激性、易怒性等が挙げられる。また、認知機能障害には、集中力、注意力及びワーキング・メモリ等を含む記憶力、遂行機能、言語流調、言語記憶、及びデュアルタスク等の低下や喪失等が挙げられる。
In this specification, the symptoms of the aftereffects of viral infection include various symptoms such as physical symptoms, mental symptoms, and cognitive dysfunction caused by brain dysfunction other than mental illness. Physical symptoms include, for example, fatigue, tiredness, headache, fever/low-grade fever, dyspnea, taste disorder, smell disorder, insomnia, daytime sleepiness, and stiff shoulders. Mental symptoms include, for example, loss of energy, loss of motivation, loss of appetite, loss of interest, irritability, and irritability. Cognitive dysfunction includes the decline or loss of concentration, attention, memory including working memory, executive function, language fluency, language memory, and dual tasking.
本明細書において「脳機能障害」とは、脳部における疾患等を原因として、思考、感情、行動等の脳機能が障害を受けることをいう。
In this specification, "brain dysfunction" refers to impairment of brain functions such as thinking, emotion, and behavior caused by a disease in the brain.
「精神疾患」とは、広義には外因性、心因性、又は内因性の脳の機能的又は器質的障害の総称をいう。しかし、本明細書において「精神疾患」とは、特に断りのない限り、精神病理学の診断カテゴリーにおいて統合失調症、うつ病、又は双極性障害に分類される3つの疾患を意味する。
"Mental illness" is, in a broad sense, a general term for exogenous, psychogenic, or endogenous functional or organic disorders of the brain. However, in this specification, unless otherwise specified, "mental illness" refers to the three disorders classified as schizophrenia, depression, or bipolar disorder in the diagnostic categories of psychopathology.
「うつ病」とは、抑うつ、気力低下、意欲低下、興味低下、食欲低下、不眠、悲哀感、罪責感、自責感、希死念慮等の症状を伴う気分障害の一種をいう。うつ病の医学的な定義はなく、一般にはアメリカ精神医学会（APA）の「精神疾患の診断・統計マニュアル第5版（Diagnostic and Statistical Manual of Mental Disorders V(DSM-5)」やWHOのInternational Classification of Diseases-10（ICD-10）等に記載の操作的診断基準において、大うつ病エピソードに合致する疾患をうつ病と診断している。具体的には、例えば、DSM-5の主要な診断を行うための半構造化面接ガイドである「DSM-5のための構造化面接（Structured Clinical Interview for DSM-5: SCID-5）」において、被験者がうつ病の基準を満たす場合、その被験者はうつ病と診断される。ただし、本明細書では、前記操作的診断基準の結果だけでなく、内因的結果からもうつ病と診断された場合をうつ病とする。なお、SCID-5の詳細については、実施例１において詳述する。
"Depression" refers to a type of mood disorder accompanied by symptoms such as low spirits, loss of energy, lack of motivation, loss of interest, loss of appetite, insomnia, sadness, feelings of guilt, self-blame, and suicidal thoughts. There is no medical definition of depression, and generally, disorders that meet the criteria for a major depressive episode are diagnosed as depression in the operational diagnostic criteria described in the Diagnostic and Statistical Manual of Mental Disorders V (DSM-5) of the American Psychiatric Association (APA) and the International Classification of Diseases-10 (ICD-10) of the WHO. Specifically, for example, if a subject meets the criteria for depression in the Structured Clinical Interview for DSM-5 (SCID-5), a semi-structured interview guide for making the main diagnoses of DSM-5, the subject is diagnosed with depression. However, in this specification, depression is defined as a condition that is diagnosed not only based on the results of the operational diagnostic criteria but also based on intrinsic results. Details of the SCID-5 will be described in Example 1.
本明細書において「内因的結果」とは、身体的変化に基づく客観的測定結果をいう。例えば、光トポグラフィー検査等を用いた脳活動に伴う大脳皮質の血中ヘモグロビン濃度変化の測定結果が挙げられる。光トポグラフィー検査は、生体が血中のヘモグロビン以外に近赤外光の大きな吸収体を持たないことを利用した近赤外線分光法（Near-Infrared Spectroscopy：NIRS）による検査であって、数値化された大脳血流量のグラフデータのパターンから、うつ病、双極性障害、統合失調症、及び健常のいずれに該当するかを客観的に判断することができる。
In this specification, "intrinsic results" refers to objective measurement results based on physical changes. For example, there are measurement results of changes in blood hemoglobin concentration in the cerebral cortex associated with brain activity using optical topography testing. Optical topography testing is a near-infrared spectroscopy (NIRS) test that takes advantage of the fact that living organisms have no significant absorbers of near-infrared light other than hemoglobin in the blood, and can objectively determine whether a patient has depression, bipolar disorder, schizophrenia, or is healthy, based on the pattern of graph data of quantified cerebral blood flow.
本明細書において「うつ病様症状」とは、一部の症状がうつ病の症状に類似するものの前記操作的診断基準及び内因的結果においてうつ病に該当しない脳機能障害を伴う症状をいう。
In this specification, "depression-like symptoms" refers to symptoms accompanied by brain dysfunction that are partially similar to symptoms of depression, but do not correspond to depression based on the operational diagnostic criteria and intrinsic results.
本明細書において「健常者」とは、健常状態にあるヒト個体をいう。本明細書において「健常状態」とは、少なくとも精神疾患及びウイルス感染後遺症を発症していない状態、好ましくは、あらゆる疾患や障害のない健全な状態を意味する。
In this specification, the term "healthy individual" refers to a human individual who is in a healthy state. In this specification, the term "healthy state" refers to a state in which at least mental illness and after-effects of viral infection have not developed, and preferably a healthy state without any illness or disorder.
「三環式化合物」とは、化学構造中に3つの環状構造を有する化合物をいう。本明細書では特に断りのない限り、両側にベンゼン環を含んだ三環式化合物を意味する。そのような構造を示す代表例として、三環系抗うつ薬等が挙げられる。
"Tricyclic compound" refers to a compound that has three ring structures in its chemical structure. In this specification, unless otherwise specified, it means a tricyclic compound that contains a benzene ring on both sides. Representative examples of such a structure include tricyclic antidepressants.
１－３．構成
本発明のウイルス感染後遺症抑制剤は、以下の一般式（I）及び／又は一般式（II)で示される三環式化合物又はその塩からなる。 1-3. Constitution The agent for suppressing sequelae of viral infection of the present invention comprises a tricyclic compound represented by the following general formula (I) and/or general formula (II) or a salt thereof.
本発明のウイルス感染後遺症抑制剤は、以下の一般式（I）及び／又は一般式（II)で示される三環式化合物又はその塩からなる。 1-3. Constitution The agent for suppressing sequelae of viral infection of the present invention comprises a tricyclic compound represented by the following general formula (I) and/or general formula (II) or a salt thereof.
本明細書において「その塩」とは、式（I）で示される三環式化合物の塩であって、酸を用いて調製された活性化合物の酸付加塩をいう。好ましくは薬学的許容される非毒性の酸付加塩である。
In this specification, "salt thereof" refers to a salt of the tricyclic compound represented by formula (I), which is an acid addition salt of the active compound prepared using an acid. It is preferably a pharma-
ceutically acceptable non-toxic acid addition salt.
酸付加塩としては、例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩、炭酸水素塩若しくは過塩素酸塩のような無機酸塩、酢酸塩、プロピオン酸塩、乳酸塩、マレイン酸塩、フマール酸塩、酒石酸塩、リンゴ酸塩、クエン酸塩若しくはアスコルビン酸塩のような有機酸塩、メタンスルホン酸塩、イセチオン酸塩、ベンゼンスルホン酸塩若しくはｐ－トルエンスルホン酸塩のようなスルホン酸塩又はアスパラギン酸塩及びグルタミン酸塩のような酸性アミノ酸等が挙げられる。
Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates, hydrogencarbonates, and perchlorates; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tartrates, malates, citrates, and ascorbates; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, and p-toluenesulfonates; and acidic amino acids such as aspartates and glutamates.
前記一般式（I）で示される三環式化合物の具体例として、以下の式（IV)～式（X）で示される三環式化合物が挙げられる。
Specific examples of the tricyclic compound represented by the general formula (I) include the tricyclic compounds represented by the following formulas (IV) to (X).
式（IV)で示される三環式化合物はクロミプラミン、式（V)で示される三環式化合物はデシプラミン、式（VI)で示される三環式化合物はイミプラミン、式（VII)で示される三環式化合物はトリミプラミン、式（VIII)で示される三環式化合物はロフェプラミン、式（IX)で示される三環式化合物はアミトリプリチン、及び式（X)で示される三環式化合物はノルトリプリチンである。
The tricyclic compound represented by formula (IV) is clomipramine, the tricyclic compound represented by formula (V) is desipramine, the tricyclic compound represented by formula (VI) is imipramine, the tricyclic compound represented by formula (VII) is trimipramine, the tricyclic compound represented by formula (VIII) is lofepramine, the tricyclic compound represented by formula (IX) is amitriptyline, and the tricyclic compound represented by formula (X) is nortriptyline.
上記式（IV)～（X)で示される三環式化合物はいずれも三環系抗うつ剤として知られる既承認薬である。しかし、前述のように本明細書においてウイルス感染後遺症は、うつ病等の精神疾患を含まない脳機能障害を原因とする症状を対象とする。したがって、従来の三環系抗うつ剤とは、その用途が異なる。
The tricyclic compounds represented by the above formulas (IV) to (X) are all already approved drugs known as tricyclic antidepressants. However, as mentioned above, in this specification, the aftereffects of viral infection refer to symptoms caused by brain dysfunction that do not include psychiatric disorders such as depression. Therefore, their uses are different from those of conventional tricyclic antidepressants.
ウイルス感染後遺症を軽減、軽快、寛解、又は治療するための抑制剤として上記三環式化合物を使用することができる。
The above tricyclic compounds can be used as inhibitors to reduce, ameliorate, ameliorate, or treat the aftereffects of viral infection.
２．ウイルス感染後遺症抑制組成物
２－１．概要
本発明の第２の態様はウイルス感染後遺症抑制組成物（本明細書では、以下、しばしば「本組成物」と略称する）である。本組成物は前記第１態様に記載のウイルス感染後遺症抑制剤を有効成分として含むことを特徴とする。本組成物によれば、ウイルス感染後遺症抑制組成物等を安定的に、また医薬組成物として、生体投与時の負荷や侵襲性を低減し、より投与しやすい形態で提供することができる。 2. Composition for suppressing sequelae of viral infection 2-1. Overview The second aspect of the present invention is a composition for suppressing sequelae of viral infection (hereinafter often abbreviated as "the composition"). The composition is characterized in that it contains the agent for suppressing sequelae of viral infection described in the first aspect as an active ingredient. According to the composition, the composition for suppressing sequelae of viral infection and the like can be stably provided as a pharmaceutical composition in a form that reduces the burden and invasiveness when administered to a living body and is easier to administer.
２－１．概要
本発明の第２の態様はウイルス感染後遺症抑制組成物（本明細書では、以下、しばしば「本組成物」と略称する）である。本組成物は前記第１態様に記載のウイルス感染後遺症抑制剤を有効成分として含むことを特徴とする。本組成物によれば、ウイルス感染後遺症抑制組成物等を安定的に、また医薬組成物として、生体投与時の負荷や侵襲性を低減し、より投与しやすい形態で提供することができる。 2. Composition for suppressing sequelae of viral infection 2-1. Overview The second aspect of the present invention is a composition for suppressing sequelae of viral infection (hereinafter often abbreviated as "the composition"). The composition is characterized in that it contains the agent for suppressing sequelae of viral infection described in the first aspect as an active ingredient. According to the composition, the composition for suppressing sequelae of viral infection and the like can be stably provided as a pharmaceutical composition in a form that reduces the burden and invasiveness when administered to a living body and is easier to administer.
２－２．構成
２－２－１．構成因子
本発明のウイルス感染後遺症抑制組成物は、必須の構成因子として有効成分を、また選択的構成因子として溶媒及び／又は担体を含む。以下、それぞれの構成因子について具体的に説明をする。 The composition for suppressing sequelae of viral infection of the present invention contains an active ingredient as an essential component, and a solvent and/or a carrier as optional components. Each of the components will be specifically described below.
２－２－１．構成因子
本発明のウイルス感染後遺症抑制組成物は、必須の構成因子として有効成分を、また選択的構成因子として溶媒及び／又は担体を含む。以下、それぞれの構成因子について具体的に説明をする。 The composition for suppressing sequelae of viral infection of the present invention contains an active ingredient as an essential component, and a solvent and/or a carrier as optional components. Each of the components will be specifically described below.
（１）有効成分
本組成物は、第１態様に記載のウイルス感染後遺症抑制剤を必須の有効成分として含む。本組成物は、1又は異なる2以上の前記ウイルス感染後遺症抑制剤を含むことができる。また、ウイルス感染後遺症又はそれ以外の疾患の抑制又は治療に有効な薬効を有する他の有効成分を含むこともできる。 (1) Active ingredient The present composition contains the agent for suppressing viral infection sequelae described in the first embodiment as an essential active ingredient. The present composition may contain one or more different agents for suppressing viral infection sequelae. The composition may also contain other active ingredients that have a medicinal effect in suppressing or treating viral infection sequelae or other diseases.
本組成物は、第１態様に記載のウイルス感染後遺症抑制剤を必須の有効成分として含む。本組成物は、1又は異なる2以上の前記ウイルス感染後遺症抑制剤を含むことができる。また、ウイルス感染後遺症又はそれ以外の疾患の抑制又は治療に有効な薬効を有する他の有効成分を含むこともできる。 (1) Active ingredient The present composition contains the agent for suppressing viral infection sequelae described in the first embodiment as an essential active ingredient. The present composition may contain one or more different agents for suppressing viral infection sequelae. The composition may also contain other active ingredients that have a medicinal effect in suppressing or treating viral infection sequelae or other diseases.
本組成物に含まれる前記ウイルス感染後遺症抑制剤の含有量は、包含されるその種類及び／又はその有効量、本組成物の剤形、後述する担体又は添加物の種類、並びに疾患の種類によって異なるため、それぞれの条件を勘案して適宜定めればよい。
The amount of the agent for suppressing the sequelae of viral infection contained in the composition varies depending on the type and/or effective amount of the agent, the dosage form of the composition, the type of carrier or additive described below, and the type of disease, and may be determined appropriately taking into account each of the conditions.
本明細書において「有効量」とは、本組成物において前記ウイルス感染後遺症抑制剤が有効成分として、その機能を発揮する上で必要な量で、かつそれを適用する生体に対して有害な副作用を、ほとんど又は全く生じない量をいう。この有効量は、被験者の情報、投与経路、及び投与回数等の様々な条件によって変化し得る。また、一日に投与される有効成分の総量（一日の投与単位）が有効量に達していればよい。したがって、本組成物は、有効成分の一日の投与単位が所定の範囲内にあれば、一日に複数回投与することもできる。
In this specification, "effective amount" refers to the amount necessary for the viral infection sequelae inhibitor to function as an active ingredient in the composition, and which causes little or no harmful side effects in the living body to which it is applied. This effective amount may vary depending on various conditions such as the subject's information, the route of administration, and the number of administrations. Furthermore, it is sufficient that the total amount of active ingredient administered per day (daily dosage unit) reaches an effective amount. Therefore, the composition can be administered multiple times per day, so long as the daily dosage unit of the active ingredient is within a specified range.
本組成物に含まれる前記ウイルス感染後遺症抑制剤の有効量は、限定はしないが、例えば、一日の投与単位中、5mg以上40mg以下、6mg以上38mg以下、7mg以上35mg以下、8mg以上30mg以下、9g以上28mg以下、10mg以上26mg以下、11mg以上24mg以下、12mg以上22mg以下、13mg以上20mg以下、14mg以上18mg以下、15mg以上16mg以下であればよい。ウイルス感染後遺症患者に対する一日の投与量が40mgを超えると、ウイルス感染後遺症とは異なる新たな副作用を生じる可能性があり、好ましくない。
一方、第１態様に記載のウイルス感染後遺症抑制剤を構成する三環式化合物を抗うつ剤として使用する場合、その投与量は、一般に、クロミプラミンであれば50mg～100mg/日（最大225mg/日）を1～3回に分割して経口投与する必要がある。また、デシプラミンであれば75mg～150mg/日を初期用量として最大300mg/日まで漸増して、イミプラミンであれば30mg～70mg/日を初期用量として200mg/日（最大300mg/日）まで漸増して、トリミプラミンであれば50mg～100mg/日を初期用量として200mg/日（最大300mg/日）まで漸増して、そしてロフェプラミンであれば10mg～25mg/回を1日2～3回、最大300mg/日まで漸増して、経口投与する必要がある。さらに、アミトリプリチンは、30mg～75mg/回を初期用量として1日150mgまで漸増して、またノルトリプリチンは、10mg～25mg/回を1日2～3回、最大150mg/日相当量以内まで漸増して経口投与する必要がある。このように、本組成物に含まれる前記ウイルス感染後遺症抑制剤は、抗うつ剤として使用する場合と比較して少量で有効性を発揮し得るため、副作用の影響も低く、コストも抑えることができる。 The effective amount of the viral infection sequelae inhibitor contained in the present composition is not limited, but may be, for example, 5 mg to 40 mg, 6 mg to 38 mg, 7 mg to 35 mg, 8 mg to 30 mg, 9 mg to 28 mg, 10 mg to 26 mg, 11 mg to 24 mg, 12 mg to 22 mg, 13 mg to 20 mg, 14 mg to 18 mg, or 15 mg to 16 mg in a daily dosage unit. If the daily dosage for a patient with viral infection sequelae exceeds 40 mg, it may cause new side effects other than viral infection sequelae, which is not preferable.
On the other hand, when the tricyclic compound constituting the inhibitor for the sequelae of viral infection described in the first embodiment is used as an antidepressant, the dosage should generally be 50mg-100mg/day (maximum 225mg/day) for clomipramine, which should be orally administered in 1-3 divided doses. Also, desipramine should be orally administered at an initial dose of 75mg-150mg/day, gradually increased to a maximum of 300mg/day, imipramine should be orally administered at an initial dose of 30mg-70mg/day, gradually increased to a maximum of 200mg/day (maximum 300mg/day), trimipramine should be orally administered at an initial dose of 50mg-100mg/day, gradually increased to a maximum of 200mg/day (maximum 300mg/day), and lofepramine should be orally administered at 10mg-25mg/time, 2-3 times a day, gradually increased to a maximum of 300mg/day. Furthermore, amitriptyline must be orally administered at an initial dose of 30-75 mg/time, gradually increasing to 150 mg/day, and nortriptyline must be orally administered at 10-25 mg/time, 2-3 times a day, gradually increasing to a maximum of 150 mg/day. Thus, the viral infection sequelae suppressant contained in the present composition can be effective in a small amount compared to when used as an antidepressant, and therefore the side effects are less and the cost can be reduced.
一方、第１態様に記載のウイルス感染後遺症抑制剤を構成する三環式化合物を抗うつ剤として使用する場合、その投与量は、一般に、クロミプラミンであれば50mg～100mg/日（最大225mg/日）を1～3回に分割して経口投与する必要がある。また、デシプラミンであれば75mg～150mg/日を初期用量として最大300mg/日まで漸増して、イミプラミンであれば30mg～70mg/日を初期用量として200mg/日（最大300mg/日）まで漸増して、トリミプラミンであれば50mg～100mg/日を初期用量として200mg/日（最大300mg/日）まで漸増して、そしてロフェプラミンであれば10mg～25mg/回を1日2～3回、最大300mg/日まで漸増して、経口投与する必要がある。さらに、アミトリプリチンは、30mg～75mg/回を初期用量として1日150mgまで漸増して、またノルトリプリチンは、10mg～25mg/回を1日2～3回、最大150mg/日相当量以内まで漸増して経口投与する必要がある。このように、本組成物に含まれる前記ウイルス感染後遺症抑制剤は、抗うつ剤として使用する場合と比較して少量で有効性を発揮し得るため、副作用の影響も低く、コストも抑えることができる。 The effective amount of the viral infection sequelae inhibitor contained in the present composition is not limited, but may be, for example, 5 mg to 40 mg, 6 mg to 38 mg, 7 mg to 35 mg, 8 mg to 30 mg, 9 mg to 28 mg, 10 mg to 26 mg, 11 mg to 24 mg, 12 mg to 22 mg, 13 mg to 20 mg, 14 mg to 18 mg, or 15 mg to 16 mg in a daily dosage unit. If the daily dosage for a patient with viral infection sequelae exceeds 40 mg, it may cause new side effects other than viral infection sequelae, which is not preferable.
On the other hand, when the tricyclic compound constituting the inhibitor for the sequelae of viral infection described in the first embodiment is used as an antidepressant, the dosage should generally be 50mg-100mg/day (maximum 225mg/day) for clomipramine, which should be orally administered in 1-3 divided doses. Also, desipramine should be orally administered at an initial dose of 75mg-150mg/day, gradually increased to a maximum of 300mg/day, imipramine should be orally administered at an initial dose of 30mg-70mg/day, gradually increased to a maximum of 200mg/day (maximum 300mg/day), trimipramine should be orally administered at an initial dose of 50mg-100mg/day, gradually increased to a maximum of 200mg/day (maximum 300mg/day), and lofepramine should be orally administered at 10mg-25mg/time, 2-3 times a day, gradually increased to a maximum of 300mg/day. Furthermore, amitriptyline must be orally administered at an initial dose of 30-75 mg/time, gradually increasing to 150 mg/day, and nortriptyline must be orally administered at 10-25 mg/time, 2-3 times a day, gradually increasing to a maximum of 150 mg/day. Thus, the viral infection sequelae suppressant contained in the present composition can be effective in a small amount compared to when used as an antidepressant, and therefore the side effects are less and the cost can be reduced.
なお、本明細書において「被験者」とは、前記ウイルス感染後遺症抑制剤又は本組成物の適用対象となるヒト生体をいう。また、「被験者の情報」とは、適用する被験者の様々な個体情報である。例えば、全身の健康状態、疾患・病害に罹患している場合にはその進行度や重症度、年齢、体重、性別、食生活、薬剤感受性、併用薬物の有無及び治療に対する耐性等を含む。本組成物における本抑制剤の有効量、及びそれに基づいて算出される適用量は、個々の被験者の情報等に応じて、最終的には医師等の判断によって決定される。
In this specification, the term "subject" refers to a human living body to which the viral infection sequelae inhibitor or the present composition is applied. Furthermore, "subject information" refers to various individual information on the subject to which the composition is applied. For example, this includes the overall health condition, the progression and severity of a disease or illness if present, age, weight, sex, diet, drug sensitivity, the presence or absence of concomitant drugs, and resistance to treatment. The effective amount of the inhibitor in the present composition, and the application amount calculated based on this, are ultimately determined by the judgment of a doctor or other professional depending on the information of each individual subject, etc.
（２）溶媒
本組成物は、薬学的に許容可能な溶媒を含むことができる。溶媒は、本組成物における選択的構成因子であり、必要に応じて添加すればよい。「薬学的に許容可能な」とは、生体に無害又は低毒性で、製剤技術分野において通常使用可能な、好ましくは医薬組成物に使用可能なことをいう。 (2) Solvent The present composition may contain a pharma- ceutically acceptable solvent. The solvent is an optional component of the present composition, and may be added as necessary. "Pharmaceutically acceptable" means that the solvent is harmless or has low toxicity to the living body, and can be generally used in the field of formulation technology, preferably in pharmaceutical compositions.
本組成物は、薬学的に許容可能な溶媒を含むことができる。溶媒は、本組成物における選択的構成因子であり、必要に応じて添加すればよい。「薬学的に許容可能な」とは、生体に無害又は低毒性で、製剤技術分野において通常使用可能な、好ましくは医薬組成物に使用可能なことをいう。 (2) Solvent The present composition may contain a pharma- ceutically acceptable solvent. The solvent is an optional component of the present composition, and may be added as necessary. "Pharmaceutically acceptable" means that the solvent is harmless or has low toxicity to the living body, and can be generally used in the field of formulation technology, preferably in pharmaceutical compositions.
溶媒には、例えば、水若しくは水溶液、又は有機溶剤が挙げられる。薬学的に許容可能な水溶液には、例えば、生理食塩水、ブドウ糖やその他の補助剤を含む等張液、リン酸塩緩衝液、酢酸ナトリウム緩衝液が挙げられる。ここでいう補助剤には、例えば、D-ソルビトール、D-マンノース、D-マンニトール、塩化ナトリウム、その他にも低濃度の非イオン性界面活性剤、ポリオキシエチレンソルビタン脂肪酸エステル類等が挙げられる。薬学的に許容可能な有機溶媒には、例えば、エタノール、ブタノール等が挙げられる。
Solvents include, for example, water or aqueous solutions, and organic solvents. Pharmaceutically acceptable aqueous solutions include, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, phosphate buffer, and sodium acetate buffer. Adjuvants here include, for example, D-sorbitol, D-mannose, D-mannitol, sodium chloride, and other low-concentration nonionic surfactants, polyoxyethylene sorbitan fatty acid esters, etc. Pharmaceutically acceptable organic solvents include, for example, ethanol, butanol, etc.
（３）担体
本組成物は、薬学的に許容可能な担体を含むことができる。担体は、本組成物における選択的構成因子であり、必要に応じて添加すればよい。 (3) Carrier The composition may contain a pharma- ceutically acceptable carrier, which is an optional component of the composition and may be added as needed.
本組成物は、薬学的に許容可能な担体を含むことができる。担体は、本組成物における選択的構成因子であり、必要に応じて添加すればよい。 (3) Carrier The composition may contain a pharma- ceutically acceptable carrier, which is an optional component of the composition and may be added as needed.
担体には、例えば、賦形剤、結合剤、崩壊剤、充填剤、懸濁剤、希釈剤、可溶化剤、分散剤、界面活性剤、乳化剤、無痛化剤、安定剤、保存剤、防腐剤、抗酸化剤、緩衝剤、増量剤、保湿剤（例えば、グリセリン、澱粉等）、吸着剤（例えば、澱粉、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等）、着色剤、香料、甘味剤、及び等張化剤等が挙げられる。
Carriers include, for example, excipients, binders, disintegrants, fillers, suspending agents, diluents, solubilizers, dispersants, surfactants, emulsifiers, soothing agents, stabilizers, preservatives, antiseptics, antioxidants, buffers, bulking agents, moisturizing agents (e.g., glycerin, starch, etc.), adsorbents (e.g., starch, lactose, kaolin, bentonite, colloidal silicic acid, etc.), colorants, flavors, sweeteners, and isotonicity agents.
このような担体は、主として剤形形成を容易にし、また剤形及び薬剤効果を維持する他、有効成分である前記ウイルス感染後遺症抑制剤が生体内での分解を受け難くするために用いられるものであって、必要に応じて適宜使用すればよい。
Such carriers are primarily used to facilitate the formation of dosage forms and maintain the dosage form and drug efficacy, as well as to make the active ingredient, the agent for suppressing viral infection sequelae, less susceptible to degradation in the body, and may be used appropriately as needed.
２－２－２．剤形
本組成物の剤形は、有効成分である前記ウイルス感染後遺症抑制剤及び他の有効成分を不活化させず、投与後に生体内で有効成分の薬理効果を発揮し得る形態であれば特に限定しない。また、本組成物の具体的な剤形は、投与法及び／又は処方条件に応じて適宜選択すればよい。一般に投与法は、経口投与と非経口投与に大別することができるが、本組成物はそれぞれの投与法に適した剤形にすればよい。 2-2-2. Dosage form The dosage form of the present composition is not particularly limited as long as it does not inactivate the active ingredient, the viral infection sequelae suppressor, and other active ingredients, and can exert the pharmacological effect of the active ingredient in the living body after administration. The specific dosage form of the present composition may be appropriately selected depending on the administration method and/or prescription conditions. In general, the administration method can be roughly divided into oral administration and parenteral administration, and the present composition may be made into a dosage form suitable for each administration method.
本組成物の剤形は、有効成分である前記ウイルス感染後遺症抑制剤及び他の有効成分を不活化させず、投与後に生体内で有効成分の薬理効果を発揮し得る形態であれば特に限定しない。また、本組成物の具体的な剤形は、投与法及び／又は処方条件に応じて適宜選択すればよい。一般に投与法は、経口投与と非経口投与に大別することができるが、本組成物はそれぞれの投与法に適した剤形にすればよい。 2-2-2. Dosage form The dosage form of the present composition is not particularly limited as long as it does not inactivate the active ingredient, the viral infection sequelae suppressor, and other active ingredients, and can exert the pharmacological effect of the active ingredient in the living body after administration. The specific dosage form of the present composition may be appropriately selected depending on the administration method and/or prescription conditions. In general, the administration method can be roughly divided into oral administration and parenteral administration, and the present composition may be made into a dosage form suitable for each administration method.
経口投与の場合、剤形としては、固形剤（錠剤、丸剤、舌下剤、カプセル剤、ドロップ剤を含む）、顆粒剤、粉剤、散剤、液剤（内用水剤、懸濁剤、乳剤、シロップ剤を含む）等が挙げられる。固形剤は、必要に応じて当該技術分野で公知の剤皮を施した剤形、例えば、糖衣錠、ゼラチン被包錠、腸溶錠、フィルムコーティング錠、二重錠、多層錠にすることができる。
For oral administration, dosage forms include solids (including tablets, pills, sublingual tablets, capsules, and drops), granules, powders, and liquids (including oral solutions, suspensions, emulsions, and syrups). Solids can be made into dosage forms with coatings known in the art, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, and multi-layered tablets, if necessary.
非経口投与の場合、全身投与及び局所投与に分けることができ、また局所投与は、さらに組織内投与、経表皮投与、経粘膜投与及び経直腸的投与にさらに細分することもできる。本組成物もそれぞれの投与法に適した剤形にすればよい。例えば、全身投与又は組織内投与に適した剤形としては、液剤である注射剤を挙げることができる。経表皮投与又は経粘膜投与に適した剤形としては、液剤（エアロゾル、塗布剤、点眼剤、点鼻剤、吸引剤を含む）、懸濁剤（乳剤、クリーム剤を含む）、粉剤（点鼻剤、吸引剤を含む）、ペースト剤、ゲル剤、軟膏剤、硬膏剤等を挙げることができる。経直腸的投与に適した剤形としては、坐剤等を挙げることができる。
Parenteral administration can be divided into systemic administration and local administration, and local administration can be further divided into intratissue administration, transepidermal administration, transmucosal administration, and transrectal administration. The composition may be in a dosage form suitable for each administration method. For example, a dosage form suitable for systemic or intratissue administration may be an injection, which is a liquid. Dosage forms suitable for transepidermal or transmucosal administration may be liquids (including aerosols, liniments, eye drops, nasal drops, and inhalants), suspensions (including emulsions and creams), powders (including nasal drops and inhalants), pastes, gels, ointments, plasters, etc. Dosage forms suitable for rectal administration may be suppositories, etc.
２－３．投与方法
本組成物の投与方法は、前述のように非経口投与と経口投与に大別することができる。経口投与は、一般に全身投与であるが、非経口投与は、さらに局所投与と全身投与に細分できる。本組成物の投与方法は、症状又は進行度等に応じて適宜選択することができ、局所的投与又は全身投与のいずれであってもよい。ウイルス感染後遺症は、うつ病様症状を呈する精神疾患以外の脳機能障害による症状であることから、その主な発症箇所は脳である。したがって、全身投与であれば、例えば、経口投与又は血管内注射を採用できる。また、局所投与であれば、注射による脳内投与を採用できる。経口投与の場合、有効成分である前記ウイルス感染後遺症抑制剤が脳関門を通過して、標的である脳にまで送達される必要があるが、後述の実施例で示すように、本組成物は、経口投与でもその効果を発揮し得る。経口投与は、侵襲性が極めて低く、投与も容易であることから、本組成物の投与方法として特に好ましい。 2-3. Method of Administration The method of administration of the present composition can be broadly divided into parenteral administration and oral administration as described above. Oral administration is generally systemic administration, but parenteral administration can be further divided into local administration and systemic administration. The method of administration of the present composition can be appropriately selected according to symptoms or the degree of progression, and may be either local administration or systemic administration. Since the aftereffects of viral infection are symptoms caused by brain dysfunction other than psychiatric disorders that exhibit depression-like symptoms, the main site of onset is the brain. Therefore, for systemic administration, for example, oral administration or intravascular injection can be adopted. Furthermore, for local administration, intracerebral administration by injection can be adopted. In the case of oral administration, the active ingredient, the viral infection aftereffect suppressant, needs to pass through the brain barrier and be delivered to the target brain, but as shown in the examples described later, the present composition can also exert its effect by oral administration. Oral administration is particularly preferable as a method of administration of the present composition because it is extremely low invasive and easy to administer.
本組成物の投与方法は、前述のように非経口投与と経口投与に大別することができる。経口投与は、一般に全身投与であるが、非経口投与は、さらに局所投与と全身投与に細分できる。本組成物の投与方法は、症状又は進行度等に応じて適宜選択することができ、局所的投与又は全身投与のいずれであってもよい。ウイルス感染後遺症は、うつ病様症状を呈する精神疾患以外の脳機能障害による症状であることから、その主な発症箇所は脳である。したがって、全身投与であれば、例えば、経口投与又は血管内注射を採用できる。また、局所投与であれば、注射による脳内投与を採用できる。経口投与の場合、有効成分である前記ウイルス感染後遺症抑制剤が脳関門を通過して、標的である脳にまで送達される必要があるが、後述の実施例で示すように、本組成物は、経口投与でもその効果を発揮し得る。経口投与は、侵襲性が極めて低く、投与も容易であることから、本組成物の投与方法として特に好ましい。 2-3. Method of Administration The method of administration of the present composition can be broadly divided into parenteral administration and oral administration as described above. Oral administration is generally systemic administration, but parenteral administration can be further divided into local administration and systemic administration. The method of administration of the present composition can be appropriately selected according to symptoms or the degree of progression, and may be either local administration or systemic administration. Since the aftereffects of viral infection are symptoms caused by brain dysfunction other than psychiatric disorders that exhibit depression-like symptoms, the main site of onset is the brain. Therefore, for systemic administration, for example, oral administration or intravascular injection can be adopted. Furthermore, for local administration, intracerebral administration by injection can be adopted. In the case of oral administration, the active ingredient, the viral infection aftereffect suppressant, needs to pass through the brain barrier and be delivered to the target brain, but as shown in the examples described later, the present composition can also exert its effect by oral administration. Oral administration is particularly preferable as a method of administration of the present composition because it is extremely low invasive and easy to administer.
以下に本発明の具体的な実施形態について、いくつかの例を挙げて示す。なお、以下の実施例では、対象となった被験者全員からインフォームドコンセントを得ている。
Below are some examples of specific embodiments of the present invention. In the following examples, informed consent was obtained from all subjects.
＜実施例１：健常者のCOVID-19後遺症における治療症例（１）＞
（目的）
健常状態からCOVID-19罹患後、ウイルス感染後遺症を発症した患者に対して、本発明のウイルス感染後遺症抑制組成物を投与し、その薬効について検証した。 <Example 1: Treatment of COVID-19 sequelae in healthy individuals (1)>
(the purpose)
The composition for suppressing viral infection sequelae of the present invention was administered to patients who were in a healthy state but had contracted COVID-19 and developed viral infection sequelae, and its efficacy was examined.
（目的）
健常状態からCOVID-19罹患後、ウイルス感染後遺症を発症した患者に対して、本発明のウイルス感染後遺症抑制組成物を投与し、その薬効について検証した。 <Example 1: Treatment of COVID-19 sequelae in healthy individuals (1)>
(the purpose)
The composition for suppressing viral infection sequelae of the present invention was administered to patients who were in a healthy state but had contracted COVID-19 and developed viral infection sequelae, and its efficacy was examined.
（方法）
・被験者： 40代のCOVID-19罹患女性
・ワクチン接種歴：ファイザー製COVID-19ワクチンを2回接種済み
・COVID-19罹患と症状：2回目ワクチン接種後、半年以上経過した後、家族感染者を介して罹患した。首の痛み、全身痛、頭痛、発熱、倦怠感等の症状が見られた。
・経過状況：療養期間の終了した陽性10日後も首や肩回りの痛み、緊張感、関節痛、疲労感が持続していた。陽性24日後、職場復帰してもデュアルタスク等の情報処理ができない、集中力低下、倦怠感、不眠等の症状が持続した。陽性39日後に受診し、身体症状（疲労感、不眠、日中の眠気、頭痛、全身倦怠感、肩や背中の張り等）、精神症状（易刺激性、興味・関心の低下、気力の低下等）、及び認知機能（集中力低下、健忘気味、動き出しが遅い、デュアルタスクができない、情報をまとめられない等）の症状が初診時に見られた。 (Method)
Subject: A woman in her 40s with COVID-19. Vaccination history: Received two doses of the Pfizer COVID-19 vaccine. COVID-19 infection and symptoms: More than six months after receiving the second dose, she contracted the virus through an infected family member. Symptoms included neck pain, generalized pain, headache, fever, and fatigue.
Progress: 10 days after the end of the recuperation period, pain in the neck and shoulders, tension, joint pain, and fatigue persisted. 24 days after testing positive, symptoms such as inability to process information such as dual tasks, decreased concentration, fatigue, and insomnia persisted even after returning to work. 39 days after testing positive, the patient visited the hospital and symptoms at the time of the initial consultation included physical symptoms (fatigue, insomnia, daytime sleepiness, headache, general fatigue, stiff shoulders and back, etc.), mental symptoms (irritability, decreased interest and concern, decreased energy, etc.), and cognitive function (decreased concentration, amnesia, slow start to movement, inability to dual tasks, inability to summarize information, etc.).
・被験者： 40代のCOVID-19罹患女性
・ワクチン接種歴：ファイザー製COVID-19ワクチンを2回接種済み
・COVID-19罹患と症状：2回目ワクチン接種後、半年以上経過した後、家族感染者を介して罹患した。首の痛み、全身痛、頭痛、発熱、倦怠感等の症状が見られた。
・経過状況：療養期間の終了した陽性10日後も首や肩回りの痛み、緊張感、関節痛、疲労感が持続していた。陽性24日後、職場復帰してもデュアルタスク等の情報処理ができない、集中力低下、倦怠感、不眠等の症状が持続した。陽性39日後に受診し、身体症状（疲労感、不眠、日中の眠気、頭痛、全身倦怠感、肩や背中の張り等）、精神症状（易刺激性、興味・関心の低下、気力の低下等）、及び認知機能（集中力低下、健忘気味、動き出しが遅い、デュアルタスクができない、情報をまとめられない等）の症状が初診時に見られた。 (Method)
Subject: A woman in her 40s with COVID-19. Vaccination history: Received two doses of the Pfizer COVID-19 vaccine. COVID-19 infection and symptoms: More than six months after receiving the second dose, she contracted the virus through an infected family member. Symptoms included neck pain, generalized pain, headache, fever, and fatigue.
Progress: 10 days after the end of the recuperation period, pain in the neck and shoulders, tension, joint pain, and fatigue persisted. 24 days after testing positive, symptoms such as inability to process information such as dual tasks, decreased concentration, fatigue, and insomnia persisted even after returning to work. 39 days after testing positive, the patient visited the hospital and symptoms at the time of the initial consultation included physical symptoms (fatigue, insomnia, daytime sleepiness, headache, general fatigue, stiff shoulders and back, etc.), mental symptoms (irritability, decreased interest and concern, decreased energy, etc.), and cognitive function (decreased concentration, amnesia, slow start to movement, inability to dual tasks, inability to summarize information, etc.).
本実施例の被験者における前記症状がうつ症状でないことを、以下の評価方法を用いて確認した。
The following evaluation method was used to confirm that the symptoms in the subjects of this example were not depressive symptoms.
（心理評価及び認知機能の評価方法）
（１）うつ症状の評価
本明細書の実施例において、うつ症状の評価には、以下の精神科診断面接による評価方法を用いた。 (Methods for psychological evaluation and cognitive function evaluation)
(1) Evaluation of Depressive Symptoms In the Examples of the present specification, the evaluation of depressive symptoms was performed using the following psychiatric diagnostic interview method.
（１）うつ症状の評価
本明細書の実施例において、うつ症状の評価には、以下の精神科診断面接による評価方法を用いた。 (Methods for psychological evaluation and cognitive function evaluation)
(1) Evaluation of Depressive Symptoms In the Examples of the present specification, the evaluation of depressive symptoms was performed using the following psychiatric diagnostic interview method.
（ａ）DSM-5のための構造化面接（Structured Clinical Interview for DSM-5: SCID-5）
SCID-5は、DSM-5の主要な診断を行うための半構造化面接ガイドである。診断ごとにモジュールA～Lで区分されており、うつ病や統合失調症、不安障害等の診断を体系的に評価することができる。各診断を決定するためには各モジュール内での基準を満たすか否かを評価する必要がある。通常、DSM-5分類及びAPAの診断基準を熟知している臨床家によって施行される。 (a) Structured Clinical Interview for DSM-5 (SCID-5)
The SCID-5 is a semi-structured interview guide for determining the major diagnoses of the DSM-5. It is divided into modules A to L for each diagnosis, and allows systematic evaluation of diagnoses such as depression, schizophrenia, and anxiety disorders. To determine each diagnosis, it is necessary to evaluate whether or not the criteria within each module are met. It is usually administered by clinicians who are familiar with the DSM-5 classification and the APA diagnostic criteria.
SCID-5は、DSM-5の主要な診断を行うための半構造化面接ガイドである。診断ごとにモジュールA～Lで区分されており、うつ病や統合失調症、不安障害等の診断を体系的に評価することができる。各診断を決定するためには各モジュール内での基準を満たすか否かを評価する必要がある。通常、DSM-5分類及びAPAの診断基準を熟知している臨床家によって施行される。 (a) Structured Clinical Interview for DSM-5 (SCID-5)
The SCID-5 is a semi-structured interview guide for determining the major diagnoses of the DSM-5. It is divided into modules A to L for each diagnosis, and allows systematic evaluation of diagnoses such as depression, schizophrenia, and anxiety disorders. To determine each diagnosis, it is necessary to evaluate whether or not the criteria within each module are met. It is usually administered by clinicians who are familiar with the DSM-5 classification and the APA diagnostic criteria.
(２）認知機能評価
本明細書の実施例において、認知機能評価には、以下の（ｂ）又は（ｃ）に記載の評価尺度又は検査法を用いた。 (2) Cognitive Function Assessment In the examples of the present specification, the cognitive function assessment was performed using the assessment scale or test method described in (b) or (c) below.
本明細書の実施例において、認知機能評価には、以下の（ｂ）又は（ｃ）に記載の評価尺度又は検査法を用いた。 (2) Cognitive Function Assessment In the examples of the present specification, the cognitive function assessment was performed using the assessment scale or test method described in (b) or (c) below.
（ｂ）統合失調症認知機能簡易検査評価尺度日本語版（Brief Assessment of Cognition in Schizophrenia Japanese version (BACS日本語版)）
BACSは、Keefeら（2004）によって開発されたもので言語性記憶、ワーキング・メモリ(作動記憶)、運動機能、注意、言語流暢性、および遂行機能を評価する6つの検査で構成される。兼田らによって日本語版が作成され（2006）、標準化されている（2013）。各項目において、性別と年代で補正されたZ scoreを算出することができ、認知機能の状態を把握することができる。 (b) Brief Assessment of Cognition in Schizophrenia Japanese version (BACS Japanese version)
BACS was developed by Keefe et al. (2004) and consists of six tests that evaluate verbal memory, working memory, motor function, attention, verbal fluency, and executive function. A Japanese version was created by Kaneda et al. (2006) and standardized (2013). For each item, a Z score adjusted for gender and age can be calculated, allowing the state of cognitive function to be understood.
BACSは、Keefeら（2004）によって開発されたもので言語性記憶、ワーキング・メモリ(作動記憶)、運動機能、注意、言語流暢性、および遂行機能を評価する6つの検査で構成される。兼田らによって日本語版が作成され（2006）、標準化されている（2013）。各項目において、性別と年代で補正されたZ scoreを算出することができ、認知機能の状態を把握することができる。 (b) Brief Assessment of Cognition in Schizophrenia Japanese version (BACS Japanese version)
BACS was developed by Keefe et al. (2004) and consists of six tests that evaluate verbal memory, working memory, motor function, attention, verbal fluency, and executive function. A Japanese version was created by Kaneda et al. (2006) and standardized (2013). For each item, a Z score adjusted for gender and age can be calculated, allowing the state of cognitive function to be understood.
なお、本実施例では、集中力低下、健忘、デュアルタスクができない、及び情報をまとめられない等の症状が認められたこと、検査による負荷軽減のため、6つの下位検査のうちワーキング・メモリ及び遂行機能に絞って評価を行った。
In this example, because symptoms such as impaired concentration, amnesia, inability to perform dual tasks, and inability to summarize information were observed, and in order to reduce the burden of the test, the evaluation was limited to working memory and executive function out of the six subtests.
(ｃ）光トポグラフィー検査（近赤外分光法（near-infrared spectroscopy: NIRS）） NIRSは、近赤外光を用いた脳機能マッピングの手法であり、近赤外光を用いて頭皮上から脳のヘモグロビンの変化を測定し、その結果から脳血液量を計測している。特にオキシヘモグロビンは脳活動を反映していると考えられており、その変化の状態と精神疾患との関係が明らかになっている。2009年には国際疾病分類（ICD-10）における統合失調症圏（F2）と気分障害圏（F3）の患者を対象とした「光トポグラフィーを用いたうつ症状の鑑別診断補助」が厚生労働省より先進医療として承認され、2014年には、保険収載されている。本実施例では52チャンネルのETG-4000の機材を使用している（https://www.innervision.co.jp/suite/hitachi/technote/110158/）。
(c) Optical topography test (near-infrared spectroscopy: NIRS) NIRS is a brain function mapping method using near-infrared light. It uses near-infrared light to measure changes in cerebral hemoglobin from the scalp, and the results are used to measure cerebral blood volume. Oxyhemoglobin in particular is thought to reflect brain activity, and the relationship between changes in the state of oxyhemoglobin and mental illness has been clarified. In 2009, the Ministry of Health, Labor and Welfare approved "Optical topography-based differential diagnosis aid for depressive symptoms" for patients with schizophrenia (F2) and mood disorder (F3) in the International Classification of Diseases (ICD-10) as advanced medical care, and in 2014 it was covered by insurance. In this example, the 52-channel ETG-4000 equipment is used (https://www.innervision.co.jp/suite/hitachi/technote/110158/).
なお、ヘモグロビン濃度変化を測定するために認知課題として、語想起課題（verbal fluency task: VFT）を実施している。VFTは、最初に30秒間「あ・い・う・え・お」と繰り返し言ってもらい、次の60秒間で、全ての平仮名のうち、いずれかの文字が20秒ごとに提示され、その頭文字で始まる言葉を思いつくだけ発語してもらう。最後に再び「あ・い・う・え・お」を繰り返して言ってもらい、その間の脳血液量を測定する。
In addition, a verbal fluency task (VFT) is administered as a cognitive task to measure changes in hemoglobin concentration. In the VFT, the subject is first asked to repeat "a, i, u, e, o" for 30 seconds, and then for the next 60 seconds, a letter from the entire hiragana alphabet is presented every 20 seconds, and the subject is asked to say as many words beginning with that letter as they can think of. Finally, the subject is asked to repeat "a, i, u, e, o" again, and cerebral blood volume is measured during this time.
（結果）
図１にクロミプラミン投与開始後の認知機能の経時的変化を、図２に光トポグラフィーによる前頭部におけるオキシヘモグロビン（oxy-Hb）量の変化を示す。 (result)
Figure 1 shows the time course of changes in cognitive function after the start of clomipramine administration, and Figure 2 shows the changes in oxyhemoglobin (oxy-Hb) levels in the forehead measured by optical topography.
図１にクロミプラミン投与開始後の認知機能の経時的変化を、図２に光トポグラフィーによる前頭部におけるオキシヘモグロビン（oxy-Hb）量の変化を示す。 (result)
Figure 1 shows the time course of changes in cognitive function after the start of clomipramine administration, and Figure 2 shows the changes in oxyhemoglobin (oxy-Hb) levels in the forehead measured by optical topography.
（１）診断結果：SCID-5に基づく評価では、うつ病の診断を下すための基準のうち、モジュールAの基準を満たさなかった。したがって、当該被験者は、うつ病の診断基準は満たさず、うつ病には該当しないと判断した。
(1) Diagnostic result: In the evaluation based on the SCID-5, the subject did not meet the criteria for Module A among the criteria for diagnosing depression. Therefore, it was determined that the subject did not meet the diagnostic criteria for depression and was not diagnosed with depression.
（２）認知機能評価（図１）
被験者のクロミプラミン服用前のワーキング・メモリ及び遂行機能は、Z-score（性別と年代を考慮し、-1.0～1.0の間を一般平均とした値）に換算、算出したところ、図１に示すように、服用開始前（pre）のワーキング・メモリは－1.7、遂行機能は0.1であった。40代女性の一般平均と比較して、遂行機能は平均値であったが、ワーキング・メモリは著しく低下していることが明らかとなった。 (2) Cognitive function assessment (Figure 1)
The working memory and executive function of the subjects before taking clomipramine were converted and calculated into Z-score (a value that takes into account gender and age and is set to the general average between -1.0 and 1.0), and as shown in Figure 1, the working memory before starting to take the drug (pre) was -1.7 and the executive function was 0.1. Compared to the general average for women in their 40s, the executive function was average, but it became clear that the working memory had significantly declined.
被験者のクロミプラミン服用前のワーキング・メモリ及び遂行機能は、Z-score（性別と年代を考慮し、-1.0～1.0の間を一般平均とした値）に換算、算出したところ、図１に示すように、服用開始前（pre）のワーキング・メモリは－1.7、遂行機能は0.1であった。40代女性の一般平均と比較して、遂行機能は平均値であったが、ワーキング・メモリは著しく低下していることが明らかとなった。 (2) Cognitive function assessment (Figure 1)
The working memory and executive function of the subjects before taking clomipramine were converted and calculated into Z-score (a value that takes into account gender and age and is set to the general average between -1.0 and 1.0), and as shown in Figure 1, the working memory before starting to take the drug (pre) was -1.7 and the executive function was 0.1. Compared to the general average for women in their 40s, the executive function was average, but it became clear that the working memory had significantly declined.
（３）光トポグラフィー検査（NIRS）を用いた脳機能の評価（図２）
検査開始から検査終了までのオキシヘモグロビン（oxy-Hb）波形の積分値から求められる重心値（Centroid Value）は、Aの本実施例の被験者で82.8、Bのうつ病患者で18.1、そしてCの健常者で84.9であった。被験者の重心値は健常者の重心値に近似する値を示した。 (3) Evaluation of brain function using near-infrared (NIRS) optical topography (Figure 2)
The centroid value calculated from the integral value of the oxyhemoglobin (oxy-Hb) waveform from the start to the end of the test was 82.8 for the subject in this example (A), 18.1 for the depressed patient (B), and 84.9 for the healthy subject (C). The centroid values of the subject were close to those of the healthy subject.
検査開始から検査終了までのオキシヘモグロビン（oxy-Hb）波形の積分値から求められる重心値（Centroid Value）は、Aの本実施例の被験者で82.8、Bのうつ病患者で18.1、そしてCの健常者で84.9であった。被験者の重心値は健常者の重心値に近似する値を示した。 (3) Evaluation of brain function using near-infrared (NIRS) optical topography (Figure 2)
The centroid value calculated from the integral value of the oxyhemoglobin (oxy-Hb) waveform from the start to the end of the test was 82.8 for the subject in this example (A), 18.1 for the depressed patient (B), and 84.9 for the healthy subject (C). The centroid values of the subject were close to those of the healthy subject.
また、NIRSでは脳のoxy-Hb量の変化が脳活動を反映することが知られている。また、脳前頭部のoxy-Hb量の変化を示す波形から精神疾患の傾向を判断することができる。図２のA～Cにおいて、実際に認知課題を開始（ａ）し、終了（ｂ）するまでの実施区間（課題享受区間：図２，a-b間）の波形を比較した結果、Bのうつ病患者では、波形がほぼフラットで脳活動に大きな変化が見られないのに対して、Aの本実施例被験者とCの健常者では、波形がプラス側に大きく変動しており、活発な脳活動が認められた。
In addition, it is known that in NIRS, changes in the amount of oxy-Hb in the brain reflect brain activity. Furthermore, the tendency towards mental illness can be judged from the waveform showing changes in the amount of oxy-Hb in the frontal area of the brain. In A to C of Figure 2, a comparison of the waveforms from the start (a) of the cognitive task to its end (b) (task-enjoyment period: Figure 2, between a and b) showed that in the depressed patient (B), the waveform was almost flat and no significant change in brain activity was observed, whereas in the subject of this example (A) and the healthy subject (C), the waveform fluctuated significantly to the positive side, indicating active brain activity.
以上の結果から、本実施例の被験者はNIRSにおいて、うつ病患者とは異なるパターンを示すことが明らかとなった。これは本実施例の被験者が内因的結果からも、うつ病ではなく、うつ病様症状を有するウイルス感染後遺症に罹患していることを示唆している。
These results make it clear that the subjects in this example showed a different pattern in NIRS than patients with depression. This suggests that the subjects in this example were not depressed, and suffered from aftereffects of a viral infection with depression-like symptoms, even based on the intrinsic results.
（４）症状経過
［治療開始（pre）］
クロミプラミンを1日10mg経口投与し、経過を観察した。
［服用1日目］
不眠の改善（中途覚醒後の再入眠が可能になった。）
［服用7日目（1ｗ）］
倦怠感や首の張りが軽減した。6日目から判断力が早くなった。
一方、ワーキング・メモリは－1.0まで改善した（図１）。
［服用14日目（2ｗ）］
不安感及び易怒性が低下した。デュアルタスクができるようになった。
ワーキング・メモリは、再び低下がみられたが、28日目には0.3まで改善した（図１）。
［服用28日目（4ｗ）］
過密な仕事も遂行し、かつ余力がある状態になった。能率的行動が可能となった。
［服用56日目（8ｗ）］
完全治癒した。 (4) Symptom progression [pre-treatment]
Clomipramine was administered orally at 10 mg per day and the patient's condition was monitored.
[First day of taking]
Improved insomnia (I was able to fall asleep again after waking up in the middle of the night)
[7th day of taking (1 week)]
Fatigue and neck stiffness have been reduced. From the sixth day, my judgement has improved.
On the other hand, working memory improved to -1.0 (Figure 1).
[14th day of taking (2 weeks)]
Decreased anxiety and irritability. Became able to dual-task.
Working memory again declined, but improved to 0.3 by day 28 (Figure 1).
[28th day of taking (4 weeks)]
We were able to carry out our overcrowded work and still have some spare capacity. It became possible to act efficiently.
[56th day of taking (8 weeks)]
Completely cured.
［治療開始（pre）］
クロミプラミンを1日10mg経口投与し、経過を観察した。
［服用1日目］
不眠の改善（中途覚醒後の再入眠が可能になった。）
［服用7日目（1ｗ）］
倦怠感や首の張りが軽減した。6日目から判断力が早くなった。
一方、ワーキング・メモリは－1.0まで改善した（図１）。
［服用14日目（2ｗ）］
不安感及び易怒性が低下した。デュアルタスクができるようになった。
ワーキング・メモリは、再び低下がみられたが、28日目には0.3まで改善した（図１）。
［服用28日目（4ｗ）］
過密な仕事も遂行し、かつ余力がある状態になった。能率的行動が可能となった。
［服用56日目（8ｗ）］
完全治癒した。 (4) Symptom progression [pre-treatment]
Clomipramine was administered orally at 10 mg per day and the patient's condition was monitored.
[First day of taking]
Improved insomnia (I was able to fall asleep again after waking up in the middle of the night)
[7th day of taking (1 week)]
Fatigue and neck stiffness have been reduced. From the sixth day, my judgement has improved.
On the other hand, working memory improved to -1.0 (Figure 1).
[14th day of taking (2 weeks)]
Decreased anxiety and irritability. Became able to dual-task.
Working memory again declined, but improved to 0.3 by day 28 (Figure 1).
[28th day of taking (4 weeks)]
We were able to carry out our overcrowded work and still have some spare capacity. It became possible to act efficiently.
[56th day of taking (8 weeks)]
Completely cured.
以上の結果から、本発明のウイルス感染後遺症抑制剤であるクロミプラミンの投与によって、うつ病様症状を呈するCOVID-19罹患後のウイルス感染後遺症が抑制され、長期投与により治癒することが立証された。
These results demonstrate that administration of clomipramine, a drug of the present invention that suppresses the aftereffects of viral infection, suppresses the aftereffects of viral infection that present with depression-like symptoms after contracting COVID-19, and that long-term administration can lead to a cure.
＜実施例２：うつ病患者のCOVID-19後遺症における治療症例（１）＞
（目的）
COVID-19罹患後、ウイルス感染後遺症を発症したうつ病患者に対して、本発明のウイルス感染後遺症抑制組成物を投与し、その薬効について検証した。 <Example 2: Treatment of COVID-19 sequelae in patients with depression (1)>
(the purpose)
The composition for suppressing viral infection sequelae of the present invention was administered to depressed patients who had developed viral infection sequelae after contracting COVID-19, and its efficacy was examined.
（目的）
COVID-19罹患後、ウイルス感染後遺症を発症したうつ病患者に対して、本発明のウイルス感染後遺症抑制組成物を投与し、その薬効について検証した。 <Example 2: Treatment of COVID-19 sequelae in patients with depression (1)>
(the purpose)
The composition for suppressing viral infection sequelae of the present invention was administered to depressed patients who had developed viral infection sequelae after contracting COVID-19, and its efficacy was examined.
（方法と結果）
・被験者：40代のCOVID-19罹患のうつ病男性
・服用薬歴：パロキセチン 10mg/日、トラゾドン 12.5mg/日、スボレキサント 20mg/日 ・ワクチン接種歴：不明
・COVID-19罹患と症状：COVID-19罹患後、味覚障害、嗅覚障害、下痢、腹痛、及び倦怠感の急性期症状を発症した。
・経過状況：陽性30日経過後も、倦怠感、腹痛、下痢（腸蠕動の亢進、硬便と軟便を繰り返す頻回の排便が1日4～5回）が持続した。陽性40日経過後、仕事の遂行力は通常通りだが、疲労しやすく、倦怠感、味覚障害が残る、情報をまとめられない等の症状がCOVID-19罹患後の受診時見られた。
・診断結果：被験者は、COVID-19罹患前から抗うつ薬によるうつ病治療を継続し、長らく寛解状態を保っていた。また、COVID-19罹患後の診察時に、DSM-5におけるうつ病エピソードを満たさなかった。したがって、この被験者の症状は、うつ症状の悪化ではなくCOVID-19後遺症であると判断した。
・治療開始：クロミプラミンを1日10mgで経口投与し、経過を観察した。 (Methods and Results)
- Subject: A depressed man in his 40s with COVID-19 - Medication history: Paroxetine 10 mg/day, trazodone 12.5 mg/day, suvorexant 20 mg/day - Vaccination history: Unknown - COVID-19 infection and symptoms: After contracting COVID-19, the patient developed acute symptoms of taste disorder, smell disorder, diarrhea, abdominal pain, and fatigue.
・Progression: Even after 30 days since testing positive, fatigue, abdominal pain, and diarrhea (increased intestinal peristalsis, frequent bowel movements with alternating hard and soft stools 4-5 times a day) continued. After 40 days since testing positive, the patient's work performance was normal, but symptoms such as fatigue, lethargy, lingering taste disorder, and inability to summarize information were observed when visiting the hospital after contracting COVID-19.
・Diagnosis: The subject had been undergoing treatment for depression with antidepressants since before he was infected with COVID-19, and had been in remission for a long time. In addition, at the time of his examination after he was infected with COVID-19, he did not meet the criteria for a major depressive episode according to the DSM-5. Therefore, the subject's symptoms were determined to be a COVID-19 sequelae, not a worsening of depressive symptoms.
-Treatment was started: Clomipramine was administered orally at 10 mg per day and the patient's progress was monitored.
・被験者：40代のCOVID-19罹患のうつ病男性
・服用薬歴：パロキセチン 10mg/日、トラゾドン 12.5mg/日、スボレキサント 20mg/日 ・ワクチン接種歴：不明
・COVID-19罹患と症状：COVID-19罹患後、味覚障害、嗅覚障害、下痢、腹痛、及び倦怠感の急性期症状を発症した。
・経過状況：陽性30日経過後も、倦怠感、腹痛、下痢（腸蠕動の亢進、硬便と軟便を繰り返す頻回の排便が1日4～5回）が持続した。陽性40日経過後、仕事の遂行力は通常通りだが、疲労しやすく、倦怠感、味覚障害が残る、情報をまとめられない等の症状がCOVID-19罹患後の受診時見られた。
・診断結果：被験者は、COVID-19罹患前から抗うつ薬によるうつ病治療を継続し、長らく寛解状態を保っていた。また、COVID-19罹患後の診察時に、DSM-5におけるうつ病エピソードを満たさなかった。したがって、この被験者の症状は、うつ症状の悪化ではなくCOVID-19後遺症であると判断した。
・治療開始：クロミプラミンを1日10mgで経口投与し、経過を観察した。 (Methods and Results)
- Subject: A depressed man in his 40s with COVID-19 - Medication history: Paroxetine 10 mg/day, trazodone 12.5 mg/day, suvorexant 20 mg/day - Vaccination history: Unknown - COVID-19 infection and symptoms: After contracting COVID-19, the patient developed acute symptoms of taste disorder, smell disorder, diarrhea, abdominal pain, and fatigue.
・Progression: Even after 30 days since testing positive, fatigue, abdominal pain, and diarrhea (increased intestinal peristalsis, frequent bowel movements with alternating hard and soft stools 4-5 times a day) continued. After 40 days since testing positive, the patient's work performance was normal, but symptoms such as fatigue, lethargy, lingering taste disorder, and inability to summarize information were observed when visiting the hospital after contracting COVID-19.
・Diagnosis: The subject had been undergoing treatment for depression with antidepressants since before he was infected with COVID-19, and had been in remission for a long time. In addition, at the time of his examination after he was infected with COVID-19, he did not meet the criteria for a major depressive episode according to the DSM-5. Therefore, the subject's symptoms were determined to be a COVID-19 sequelae, not a worsening of depressive symptoms.
-Treatment was started: Clomipramine was administered orally at 10 mg per day and the patient's progress was monitored.
（症状経過）
［服用5日目］
腹痛や下痢等の消化器症状の急激な改善が認められた。
［服用7日目］
消化器症状は消失した。便も良好な硬さ、頻度、量となり、排便コントロールも完全に改善した。
7日目よりクロミプラミンの投与量を20mg/日に増量した。
［服用14日目］
味覚障害は消失した。倦怠感も改善し始めた。
14日目よりクロミプラミンの投与量を30mg/日にさらに増量した。
［服用28日目］
倦怠感は消失した。一方、性欲低下（射精困難）、硬便への違和感、及び軽度鎮静等の副作用が出現した。
28日目よりクロミプラミンの投与量を20mg/日に減量した。
［服用42日目］
前記副作用は消失し、排便コントロールも良好、倦怠感はなく、生活リズムの乱れもない。その後も服用を継続しており、良好な状態を維持できている。 (Progression of symptoms)
[5th day of taking]
A rapid improvement in gastrointestinal symptoms such as abdominal pain and diarrhea was observed.
[7th day of taking]
The gastrointestinal symptoms disappeared. Stool consistency, frequency and quantity were good, and bowel control was completely improved.
From the 7th day, the dose of clomipramine was increased to 20 mg/day.
[14th day of taking]
The taste disorder disappeared. The fatigue also began to improve.
From the 14th day, the dose of clomipramine was further increased to 30 mg/day.
[28th day of taking]
The fatigue disappeared, but side effects such as decreased libido (ejaculation difficulty), discomfort with hard stools, and mild sedation appeared.
From the 28th day, the dose of clomipramine was reduced to 20 mg/day.
[42nd day of taking]
The side effects disappeared, bowel control was good, there was no fatigue, and no disruption of daily rhythm. The patient has continued taking the drug since then and is in good condition.
［服用5日目］
腹痛や下痢等の消化器症状の急激な改善が認められた。
［服用7日目］
消化器症状は消失した。便も良好な硬さ、頻度、量となり、排便コントロールも完全に改善した。
7日目よりクロミプラミンの投与量を20mg/日に増量した。
［服用14日目］
味覚障害は消失した。倦怠感も改善し始めた。
14日目よりクロミプラミンの投与量を30mg/日にさらに増量した。
［服用28日目］
倦怠感は消失した。一方、性欲低下（射精困難）、硬便への違和感、及び軽度鎮静等の副作用が出現した。
28日目よりクロミプラミンの投与量を20mg/日に減量した。
［服用42日目］
前記副作用は消失し、排便コントロールも良好、倦怠感はなく、生活リズムの乱れもない。その後も服用を継続しており、良好な状態を維持できている。 (Progression of symptoms)
[5th day of taking]
A rapid improvement in gastrointestinal symptoms such as abdominal pain and diarrhea was observed.
[7th day of taking]
The gastrointestinal symptoms disappeared. Stool consistency, frequency and quantity were good, and bowel control was completely improved.
From the 7th day, the dose of clomipramine was increased to 20 mg/day.
[14th day of taking]
The taste disorder disappeared. The fatigue also began to improve.
From the 14th day, the dose of clomipramine was further increased to 30 mg/day.
[28th day of taking]
The fatigue disappeared, but side effects such as decreased libido (ejaculation difficulty), discomfort with hard stools, and mild sedation appeared.
From the 28th day, the dose of clomipramine was reduced to 20 mg/day.
[42nd day of taking]
The side effects disappeared, bowel control was good, there was no fatigue, and no disruption of daily rhythm. The patient has continued taking the drug since then and is in good condition.
以上の結果から、抗うつ剤を服用し、うつ病に関して既に寛解状態となっており、かつCOVID-19罹患後のウイルス感染後遺症に罹患しているうつ病患者に、本発明のウイルス感染後遺症抑制剤であるクロミプラミンの投与することで、ウイルス感染後遺症が抑制されることが立証された。
These results demonstrate that administering clomipramine, a drug for suppressing viral infection sequelae of the present invention, to depressed patients who are taking antidepressants, are already in remission from depression, and are suffering from the aftereffects of viral infection after contracting COVID-19, suppresses the aftereffects of viral infection.
＜実施例３：うつ病患者のCOVID-19後遺症における治療症例（２）＞
（目的）
COVID-19罹患後、ウイルス感染後遺症を発症したうつ病患者に対して、本発明のウイルス感染後遺症抑制組成物を投与し、その薬効について検証した。 <Example 3: Treatment of COVID-19 sequelae in patients with depression (2)>
(the purpose)
The composition for suppressing viral infection sequelae of the present invention was administered to depressed patients who had developed viral infection sequelae after contracting COVID-19, and its efficacy was examined.
（目的）
COVID-19罹患後、ウイルス感染後遺症を発症したうつ病患者に対して、本発明のウイルス感染後遺症抑制組成物を投与し、その薬効について検証した。 <Example 3: Treatment of COVID-19 sequelae in patients with depression (2)>
(the purpose)
The composition for suppressing viral infection sequelae of the present invention was administered to depressed patients who had developed viral infection sequelae after contracting COVID-19, and its efficacy was examined.
（方法と結果）
・被験者：40代のCOVID-19罹患のパニック障害を併発した軽度うつ病女性
・服用薬歴：エスシタロプラム 10mg/日、クロナゼパム 0.25mg/日
・ワクチン接種歴：COVID-19ワクチンを2回接種済み
・COVID-19罹患と症状：2回目ワクチン接種後、家族感染者を介して罹患した。咳、発熱と共に、日ごとに倦怠感が増強した。呼吸困難で不眠になった後、酸素飽和度（SpO2）が92％となり発症7日目に入院し、直後より酸素投与開始した。左頸部よりIVH（中心静脈栄養）管理を行い、ICUで2週間、その後一般床で2週間入院した。
・経過状況：退院後は3週間程度、倦怠感、動作時の呼吸困難、胸の苦しさが続いた。精神的には安定していたが、倦怠感の改善と共に嗅覚障害と味覚障害が出現した。
・診断結果：実施例２の場合と同様に、被験者は、COVID-19罹患前から抗うつ薬によるうつ病治療を継続し、長らく寛解状態を保っていた。また、COVID-19罹患後の診察時に、DSM-5におけるうつ病エピソードを満たさなかった。したがって、この被験者の症状は、うつ症状の悪化ではなくCOVID-19後遺症であると判断した。
・治療開始：クロミプラミンを1日10mgで経口投与し、経過を観察した。 (Methods and Results)
Subject: A woman in her 40s with mild depression and panic disorder who was infected with COVID-19. Medication history: escitalopram 10mg/day, clonazepam 0.25mg/day. Vaccination history: Received two doses of COVID-19 vaccine. COVID-19 infection and symptoms: After receiving the second dose of the vaccine, she contracted the virus through a family member who was infected. Her fatigue worsened day by day, along with coughing and fever. After difficulty breathing and insomnia, her oxygen saturation ( SpO2 ) reached 92% and she was hospitalized on the seventh day after onset, and oxygen administration was started immediately after. She was administered IVH (total parenteral nutrition) from the left neck, and was hospitalized in the ICU for two weeks, followed by two weeks on a general bed.
Progression: After being discharged from the hospital, fatigue, difficulty breathing during movement, and chest tightness continued for about three weeks. Although mentally stable, the patient developed olfactory and tasting disorders as the fatigue improved.
・Diagnosis result: As in Example 2, the subject had been undergoing treatment for depression with antidepressants since before COVID-19 infection and had been in remission for a long time. In addition, at the time of examination after COVID-19 infection, the subject did not meet the criteria for a depressive episode in DSM-5. Therefore, the subject's symptoms were determined to be COVID-19 sequelae rather than a worsening of depressive symptoms.
-Treatment was started: Clomipramine was administered orally at 10 mg per day and the patient's progress was monitored.
・被験者：40代のCOVID-19罹患のパニック障害を併発した軽度うつ病女性
・服用薬歴：エスシタロプラム 10mg/日、クロナゼパム 0.25mg/日
・ワクチン接種歴：COVID-19ワクチンを2回接種済み
・COVID-19罹患と症状：2回目ワクチン接種後、家族感染者を介して罹患した。咳、発熱と共に、日ごとに倦怠感が増強した。呼吸困難で不眠になった後、酸素飽和度（SpO2）が92％となり発症7日目に入院し、直後より酸素投与開始した。左頸部よりIVH（中心静脈栄養）管理を行い、ICUで2週間、その後一般床で2週間入院した。
・経過状況：退院後は3週間程度、倦怠感、動作時の呼吸困難、胸の苦しさが続いた。精神的には安定していたが、倦怠感の改善と共に嗅覚障害と味覚障害が出現した。
・診断結果：実施例２の場合と同様に、被験者は、COVID-19罹患前から抗うつ薬によるうつ病治療を継続し、長らく寛解状態を保っていた。また、COVID-19罹患後の診察時に、DSM-5におけるうつ病エピソードを満たさなかった。したがって、この被験者の症状は、うつ症状の悪化ではなくCOVID-19後遺症であると判断した。
・治療開始：クロミプラミンを1日10mgで経口投与し、経過を観察した。 (Methods and Results)
Subject: A woman in her 40s with mild depression and panic disorder who was infected with COVID-19. Medication history: escitalopram 10mg/day, clonazepam 0.25mg/day. Vaccination history: Received two doses of COVID-19 vaccine. COVID-19 infection and symptoms: After receiving the second dose of the vaccine, she contracted the virus through a family member who was infected. Her fatigue worsened day by day, along with coughing and fever. After difficulty breathing and insomnia, her oxygen saturation ( SpO2 ) reached 92% and she was hospitalized on the seventh day after onset, and oxygen administration was started immediately after. She was administered IVH (total parenteral nutrition) from the left neck, and was hospitalized in the ICU for two weeks, followed by two weeks on a general bed.
Progression: After being discharged from the hospital, fatigue, difficulty breathing during movement, and chest tightness continued for about three weeks. Although mentally stable, the patient developed olfactory and tasting disorders as the fatigue improved.
・Diagnosis result: As in Example 2, the subject had been undergoing treatment for depression with antidepressants since before COVID-19 infection and had been in remission for a long time. In addition, at the time of examination after COVID-19 infection, the subject did not meet the criteria for a depressive episode in DSM-5. Therefore, the subject's symptoms were determined to be COVID-19 sequelae rather than a worsening of depressive symptoms.
-Treatment was started: Clomipramine was administered orally at 10 mg per day and the patient's progress was monitored.
（症状経過）
［服用7日目］
自覚的に85％まで嗅覚が改善し、同時に味覚・食欲も回復傾向が見られた。
［服用14日目］
ゴルフのハーフラウンドをまわれるほどに体力が回復した。
［服用28日目］
倦怠感、味覚、及び嗅覚が完全回復し、内服中止とした。1年経過後も再発はない。 (Progression of symptoms)
[7th day of taking]
The patient's sense of smell was subjectively improved by 85%, and at the same time, his sense of taste and appetite also showed a tendency to improve.
[14th day of taking]
I had recovered enough strength to play a half round of golf.
[28th day of taking]
The patient's fatigue, sense of taste, and sense of smell were completely resolved, and the medication was discontinued. There has been no recurrence even after one year.
［服用7日目］
自覚的に85％まで嗅覚が改善し、同時に味覚・食欲も回復傾向が見られた。
［服用14日目］
ゴルフのハーフラウンドをまわれるほどに体力が回復した。
［服用28日目］
倦怠感、味覚、及び嗅覚が完全回復し、内服中止とした。1年経過後も再発はない。 (Progression of symptoms)
[7th day of taking]
The patient's sense of smell was subjectively improved by 85%, and at the same time, his sense of taste and appetite also showed a tendency to improve.
[14th day of taking]
I had recovered enough strength to play a half round of golf.
[28th day of taking]
The patient's fatigue, sense of taste, and sense of smell were completely resolved, and the medication was discontinued. There has been no recurrence even after one year.
＜実施例４：うつ病患者のワクチン後遺症における治療症例＞
（目的）
COVID-19ワクチン接種後にワクチン後遺症を発症したCOVID-19非感染のうつ病患者に対し、本発明のウイルス感染後遺症抑制組成物を投与し、その薬効について検証した。 Example 4: Treatment of vaccine sequelae in patients with depression
(the purpose)
The composition for suppressing viral infection sequelae of the present invention was administered to non-COVID-19 infected depressed patients who developed vaccine sequelae after receiving the COVID-19 vaccine, and its efficacy was examined.
（目的）
COVID-19ワクチン接種後にワクチン後遺症を発症したCOVID-19非感染のうつ病患者に対し、本発明のウイルス感染後遺症抑制組成物を投与し、その薬効について検証した。 Example 4: Treatment of vaccine sequelae in patients with depression
(the purpose)
The composition for suppressing viral infection sequelae of the present invention was administered to non-COVID-19 infected depressed patients who developed vaccine sequelae after receiving the COVID-19 vaccine, and its efficacy was examined.
（方法と結果）
・被験者： 50代のCOVID-19非感染のうつ病男性
・服用薬歴：ミルタザピン 30mg/日、ニトラゼパム 1mg/日、スルピリド 300mg/日、酸化マグネシウム 330mg/日、メトクロプラミド 15mg/日、ロラゼパム 0.5mg/回頓服
・ワクチン接種歴： COVID-19ワクチンを2回接種済み
・ワクチン接種後の症状：2回目のワクチン接種後に発熱し、約1か月持続した。その後、解熱はしたものの未体験の倦怠感が続いた。この間、PCR検査は全て陰性であった。味覚障害、嗅覚障害、頭痛、消化器症状は認められず、また抑うつ気分はないものの、全身倦怠感が著しく気力が出ない、行動できない症状が1日中、変化なく続いた。
・診断結果：ワクチン接種後の初外来時も倦怠感を認め（10/10段階）、時間的にワクチン接種によるワクチン後遺症と判断した。
・治療開始：クロミプラミンを1日10mgで経口投与し、経過を観察した。 (Methods and Results)
・Subject: A depressed man in his 50s who was not infected with COVID-19 ・Medication history: Mirtazapine 30mg/day, Nitrazepam 1mg/day, Sulpiride 300mg/day, Magnesium oxide 330mg/day, Metoclopramide 15mg/day, Lorazepam 0.5mg/as-needed ・Vaccine history: Received two doses of COVID-19 vaccine ・Symptoms after vaccination: After the second vaccination, the patient developed a fever and continued for about a month. After that, the fever subsided, but the patient continued to feel fatigued, which he had never experienced before. During this time, all PCR tests were negative. There was no taste disorder, smell disorder, headache, or digestive symptoms, and the patient did not feel depressed, but the patient had a severe general fatigue and was unable to act, which continued without change throughout the day.
-Diagnosis result: Fatigue was observed at the first outpatient visit after receiving the vaccine (scale: 10/10), and given the timing, it was determined to be a vaccine aftereffect due to the vaccination.
-Treatment was started: Clomipramine was administered orally at 10 mg per day and the patient's progress was monitored.
・被験者： 50代のCOVID-19非感染のうつ病男性
・服用薬歴：ミルタザピン 30mg/日、ニトラゼパム 1mg/日、スルピリド 300mg/日、酸化マグネシウム 330mg/日、メトクロプラミド 15mg/日、ロラゼパム 0.5mg/回頓服
・ワクチン接種歴： COVID-19ワクチンを2回接種済み
・ワクチン接種後の症状：2回目のワクチン接種後に発熱し、約1か月持続した。その後、解熱はしたものの未体験の倦怠感が続いた。この間、PCR検査は全て陰性であった。味覚障害、嗅覚障害、頭痛、消化器症状は認められず、また抑うつ気分はないものの、全身倦怠感が著しく気力が出ない、行動できない症状が1日中、変化なく続いた。
・診断結果：ワクチン接種後の初外来時も倦怠感を認め（10/10段階）、時間的にワクチン接種によるワクチン後遺症と判断した。
・治療開始：クロミプラミンを1日10mgで経口投与し、経過を観察した。 (Methods and Results)
・Subject: A depressed man in his 50s who was not infected with COVID-19 ・Medication history: Mirtazapine 30mg/day, Nitrazepam 1mg/day, Sulpiride 300mg/day, Magnesium oxide 330mg/day, Metoclopramide 15mg/day, Lorazepam 0.5mg/as-needed ・Vaccine history: Received two doses of COVID-19 vaccine ・Symptoms after vaccination: After the second vaccination, the patient developed a fever and continued for about a month. After that, the fever subsided, but the patient continued to feel fatigued, which he had never experienced before. During this time, all PCR tests were negative. There was no taste disorder, smell disorder, headache, or digestive symptoms, and the patient did not feel depressed, but the patient had a severe general fatigue and was unable to act, which continued without change throughout the day.
-Diagnosis result: Fatigue was observed at the first outpatient visit after receiving the vaccine (scale: 10/10), and given the timing, it was determined to be a vaccine aftereffect due to the vaccination.
-Treatment was started: Clomipramine was administered orally at 10 mg per day and the patient's progress was monitored.
（症状経過）
［服用7日目］
7日目よりクロミプラミンを1日20mgへ増量したところ、増量2日後に倦怠感が著しく改善した（2/10段階）。一方、服用しなかった日の翌日は倦怠感の増悪（6/10段階）が認められた。現在も20mgの服用を継続し、倦怠感は再発していない。
＜実施例５：健常者のCOVID-19後遺症における治療症例（２）＞
（目的）
健常状態からCOVID-19罹患後、ウイルス感染後遺症を発症した、実施例１とは異なる年齢層の患者に対して、その薬効について検証した。
（方法）
・被験者： 50代のCOVID-19罹患女性
・ワクチン接種歴：ファイザー製COVID-19ワクチンを3回接種済み
・COVID-19罹患と症状：3回目ワクチン接種後、COVID-19が流行していた職場内で罹患した。咳が出始めたが職場での抗原検査では陰性であった。帰宅後、38度台の発熱があり、翌日PCR検査にて陽性判定された。
・急性期症状：発熱、咳、息苦しさ、倦怠感、頭痛、味覚障害、嗅覚障害、酸素飽和度（SpO2）88％まで低下した。
・経過状況：2月上旬に罹患し、療養期間の終了した陽性10日後も咳や息苦しさ、食欲低下があり、咳のため会話もままならい状態であったため、2月末まで自宅療養となった。その後、半日勤務を2週間実施した後、フルタイム勤務となるも息苦しさ、咳症状7月頃まで継続し、9月には労作時に意識消失して転倒した。10月上旬転院後、初診時の症状として、倦怠感（安静時、活動時）、咳、胸の圧迫感、呼吸困難、断眠、認知機能障害、不安、頭痛、耳鳴り等の症状が報告された。労作時呼吸困難は、動き続けたり話し続けると発症しやすく、SpO2が93％まで下がることがあった。なお、胸部CTにて肺の状態を確認したところ明らかな所見は認めらなかった。
本実施例の被験者における前記症状がうつ症状でないことを、実施例１の評価方法を用いて確認した。
（結果）
(１）診断結果
(a）SCID-5に基づくうつ症状の評価では、うつ病の診断を下すための基準を満たさなかったことから、うつ病には該当しないと判断した。
(b）認知機能評価では、クロミプラミン服用前の認知機能は、Z-score（性別と年代を考慮し、－1.0～1.0の間を一般平均とした値）に換算、算出したところ、言語流暢性が－1.30と最も低く、次いでワーキング・メモリが－0.96であった。この結果から被験者は、50代女性の一般平均と比較して、言語流暢性が著しく低下していることが明らかとなった。
(２）症状経過
［治療開始（服用0日目)]
クロミプラミンを1日10mg経口投与し、経過を観察した。
［服用13日目（2週）〕
身体症状、認知機能障害等、若干の変化がみられたが、さらなる改善を目指してクロミプラミンを1日20mgに増量して経過を観察した。
［服用27日目（4週)]
主観的評価で最大悪化時を100としたときに、労作時呼吸困難が20にまで劇的に改善した。同様にブレインフォグ（頭のボンヤリした感覚）、認知機能障害（処理速度、集中力）、及び遂行機能障害は30にまで改善した。また、倦怠感も70に改善した。
［服用41日目（6週)]
ブレインフォグ、認知機能障害、及び遂行機能障害が、さらに10まで改善した。認知機能評価（BACS）を実施したところ、言語流暢性は－1.03から－0.47まで改善しており、また情報処理速度も0.02から0.31に改善した。
［服用56日目（8週)]
上記改善が見られた症状に対して、倦怠感については依然クリアな感覚がなく、また睡眠障害も改善していなかった。そこで、クロミプラミンを1日30mgまで増量して経過を観察した。
［服用69日目（10週)]
倦怠感は、最大悪化時100から20にまで劇的に減少した、ぐったり感がなくなり、動き続けることができるようになった。不眠も改善し、起床時の感覚が良くなった。ブレインフォグ、認知機能、及び遂行機能障害についても、その後の異常は見られなかった。
［服用78日目（11週)]
全ての症状が改善し、仕事もCOVID-19罹患時以前とほぼ同等に遂行できている。認知機能評価（BACS）では、治療前に－1.30であった言語流暢性が－0.16まで改善し、情報処理速度は治療前の0.02から0.80に、また言語記憶は治療前の－0.25から1.01にまで大幅に改善した。
＜実施例６：健常者のCOVID-19後遺症における治療症例（３）＞
（目的と方法）
さらに、健常状態からCOVID-19罹患後、ウイルス感染後遺症を発症した、20代及び50代の女性患者に対して、その薬効について検証した。
SCID-5に基づくうつ症状の評価では、COVID-19発症前は、うつ病の診断を下すための基準を満たさなかったことから、両者ともに、うつ病には該当しないと判断した。しかし、罹患後、いずれも抑うつ状態になった。
基本的方法は、実施例１及び５に準じた。初期投与量はクロミプラミンを1日10mgの経口投与とした。
20代女性は、10mgの投与のまま、その後、いずれの症状も軽快した。50代女性は倦怠感や不眠については改善が認められたが、COVID-19罹患後に表出した不安や焦燥等の症状については服用11週目で若干の改善しか認められなかったため、さらなる改善を目指してクロミプラミンを1日20mgに増量して経過を観察した。その結果、劇的に改善し、その後、完治した。 (Progression of symptoms)
[7th day of taking]
On the seventh day, the dose of clomipramine was increased to 20 mg per day, and fatigue improved significantly two days after the dose increase (2/10 scale). However, fatigue worsened (6/10 scale) on the day after not taking the drug. Currently, the patient is still taking 20 mg, and fatigue has not recurred.
<Example 5: Treatment of COVID-19 sequelae in healthy individuals (2)>
(the purpose)
The efficacy of the drug was examined in patients of a different age group from that in Example 1 who were in a healthy state but contracted COVID-19 and developed sequelae of viral infection.
(Method)
Subject: A woman in her 50s with COVID-19. Vaccination history: Received three doses of the Pfizer COVID-19 vaccine. COVID-19 infection and symptoms: After receiving the third dose of the vaccine, she contracted the virus at work, where COVID-19 was prevalent. She began coughing, but an antigen test at work was negative. After returning home, she developed a fever of around 38 degrees, and a PCR test the next day determined that she was positive.
- Acute symptoms: fever, cough, shortness of breath, fatigue, headache, loss of taste and smell, oxygen saturation ( SpO2 ) decreased to 88%.
・Progression: The patient was diagnosed in early February, and even 10 days after the end of the recuperation period, he still had coughing, shortness of breath, and loss of appetite. He was unable to speak due to his cough, so he was recuperating at home until the end of February. After that, he worked half-days for two weeks, and then returned to full-time work, but his shortness of breath and coughing symptoms continued until around July, and in September he lost consciousness while exerting himself and fell. After being transferred to another hospital in early October, his symptoms at the time of his first visit included fatigue (at rest and while active), coughing, chest tightness, dyspnea, insomnia, cognitive impairment, anxiety, headache, and tinnitus. Dyspnea during exertion is likely to occur when the patient continues to move or talk, and SpO2 can drop to as low as 93%. A chest CT scan to check the condition of the lungs revealed no obvious findings.
It was confirmed using the evaluation method of Example 1 that the symptoms in the subjects of this example were not depressive symptoms.
(result)
(1) Diagnostic results (a) The evaluation of depressive symptoms based on the SCID-5 did not meet the criteria for diagnosing depression, and therefore it was determined that the patient did not have depression.
(b) In the cognitive function evaluation, the subjects' cognitive functions before taking clomipramine were converted and calculated into Z-scores (a value between -1.0 and 1.0, taking into account gender and age, with the general average being used). Verbal fluency was the lowest at -1.30, followed by working memory at -0.96. These results revealed that the subjects' verbal fluency had declined significantly compared to the general average for women in their 50s.
(2) Symptom progression [start of treatment (day 0)]
Clomipramine was administered orally at 10 mg per day and the patient's condition was monitored.
[13th day of taking the drug (2 weeks)]
Although some changes were observed in physical symptoms and cognitive impairment, the dose of clomipramine was increased to 20 mg per day in an attempt to achieve further improvement, and the patient's progress was monitored.
[27th day of taking the drug (4 weeks)]
On a subjective scale of 100, dyspnea on exertion improved dramatically to 20. Similarly, brain fog, cognitive impairment (speed of processing, ability to concentrate), and executive dysfunction improved to 30. Fatigue also improved to 70.
[Day 41 (6 weeks)]
Brain fog, cognitive impairment, and executive dysfunction further improved to 10. A cognitive assessment (BACS) was performed, with verbal fluency improving from -1.03 to -0.47, and information processing speed improving from 0.02 to 0.31.
[56th day of taking the drug (8th week)]
Although the above symptoms were improved, the patient still had no clear feeling about fatigue, and the sleep disorder had not improved. Therefore, the dose of clomipramine was increased to 30 mg per day and the progress was observed.
[69th day of taking the drug (10th week)]
Fatigue was dramatically reduced from 100 at its worst to 20, the feeling of exhaustion disappeared, and the patient was able to continue moving. Insomnia was also improved, and the patient felt better upon waking. There were no further abnormalities in brain fog, cognitive function, or executive dysfunction.
[78th day of taking the drug (11th week)]
All symptoms have improved, and the patient is able to perform work at almost the same level as before COVID-19. Cognitive function assessment (BACS) showed that verbal fluency improved from -1.30 before treatment to -0.16, information processing speed improved from 0.02 before treatment to 0.80, and verbal memory improved significantly from -0.25 before treatment to 1.01.
<Example 6: Treatment of COVID-19 sequelae in healthy individuals (3)>
(Objectives and Methods)
In addition, the efficacy of the drug was examined in female patients in their 20s and 50s who had previously been healthy but had contracted COVID-19 and subsequently developed aftereffects of the viral infection.
According to the SCID-5 evaluation of depressive symptoms, neither patient met the criteria for a diagnosis of depression before developing COVID-19, and therefore neither patient was considered to have depression. However, after contracting COVID-19, both patients became depressed.
The basic method was the same as in Examples 1 and 5. The initial dose of clomipramine was 10 mg per day, administered orally.
The woman in her 20s continued to receive 10 mg of the drug, and all symptoms subsequently improved. The woman in her 50s saw improvements in her fatigue and insomnia, but only slight improvements in symptoms such as anxiety and restlessness that appeared after contracting COVID-19 after 11 weeks of taking the drug. In order to achieve further improvement, she increased her clomipramine dose to 20 mg per day and monitored her progress. As a result, her symptoms improved dramatically, and she was subsequently cured.
［服用7日目］
7日目よりクロミプラミンを1日20mgへ増量したところ、増量2日後に倦怠感が著しく改善した（2/10段階）。一方、服用しなかった日の翌日は倦怠感の増悪（6/10段階）が認められた。現在も20mgの服用を継続し、倦怠感は再発していない。
＜実施例５：健常者のCOVID-19後遺症における治療症例（２）＞
（目的）
健常状態からCOVID-19罹患後、ウイルス感染後遺症を発症した、実施例１とは異なる年齢層の患者に対して、その薬効について検証した。
（方法）
・被験者： 50代のCOVID-19罹患女性
・ワクチン接種歴：ファイザー製COVID-19ワクチンを3回接種済み
・COVID-19罹患と症状：3回目ワクチン接種後、COVID-19が流行していた職場内で罹患した。咳が出始めたが職場での抗原検査では陰性であった。帰宅後、38度台の発熱があり、翌日PCR検査にて陽性判定された。
・急性期症状：発熱、咳、息苦しさ、倦怠感、頭痛、味覚障害、嗅覚障害、酸素飽和度（SpO2）88％まで低下した。
・経過状況：2月上旬に罹患し、療養期間の終了した陽性10日後も咳や息苦しさ、食欲低下があり、咳のため会話もままならい状態であったため、2月末まで自宅療養となった。その後、半日勤務を2週間実施した後、フルタイム勤務となるも息苦しさ、咳症状7月頃まで継続し、9月には労作時に意識消失して転倒した。10月上旬転院後、初診時の症状として、倦怠感（安静時、活動時）、咳、胸の圧迫感、呼吸困難、断眠、認知機能障害、不安、頭痛、耳鳴り等の症状が報告された。労作時呼吸困難は、動き続けたり話し続けると発症しやすく、SpO2が93％まで下がることがあった。なお、胸部CTにて肺の状態を確認したところ明らかな所見は認めらなかった。
本実施例の被験者における前記症状がうつ症状でないことを、実施例１の評価方法を用いて確認した。
（結果）
(１）診断結果
(a）SCID-5に基づくうつ症状の評価では、うつ病の診断を下すための基準を満たさなかったことから、うつ病には該当しないと判断した。
(b）認知機能評価では、クロミプラミン服用前の認知機能は、Z-score（性別と年代を考慮し、－1.0～1.0の間を一般平均とした値）に換算、算出したところ、言語流暢性が－1.30と最も低く、次いでワーキング・メモリが－0.96であった。この結果から被験者は、50代女性の一般平均と比較して、言語流暢性が著しく低下していることが明らかとなった。
(２）症状経過
［治療開始（服用0日目)]
クロミプラミンを1日10mg経口投与し、経過を観察した。
［服用13日目（2週）〕
身体症状、認知機能障害等、若干の変化がみられたが、さらなる改善を目指してクロミプラミンを1日20mgに増量して経過を観察した。
［服用27日目（4週)]
主観的評価で最大悪化時を100としたときに、労作時呼吸困難が20にまで劇的に改善した。同様にブレインフォグ（頭のボンヤリした感覚）、認知機能障害（処理速度、集中力）、及び遂行機能障害は30にまで改善した。また、倦怠感も70に改善した。
［服用41日目（6週)]
ブレインフォグ、認知機能障害、及び遂行機能障害が、さらに10まで改善した。認知機能評価（BACS）を実施したところ、言語流暢性は－1.03から－0.47まで改善しており、また情報処理速度も0.02から0.31に改善した。
［服用56日目（8週)]
上記改善が見られた症状に対して、倦怠感については依然クリアな感覚がなく、また睡眠障害も改善していなかった。そこで、クロミプラミンを1日30mgまで増量して経過を観察した。
［服用69日目（10週)]
倦怠感は、最大悪化時100から20にまで劇的に減少した、ぐったり感がなくなり、動き続けることができるようになった。不眠も改善し、起床時の感覚が良くなった。ブレインフォグ、認知機能、及び遂行機能障害についても、その後の異常は見られなかった。
［服用78日目（11週)]
全ての症状が改善し、仕事もCOVID-19罹患時以前とほぼ同等に遂行できている。認知機能評価（BACS）では、治療前に－1.30であった言語流暢性が－0.16まで改善し、情報処理速度は治療前の0.02から0.80に、また言語記憶は治療前の－0.25から1.01にまで大幅に改善した。
＜実施例６：健常者のCOVID-19後遺症における治療症例（３）＞
（目的と方法）
さらに、健常状態からCOVID-19罹患後、ウイルス感染後遺症を発症した、20代及び50代の女性患者に対して、その薬効について検証した。
SCID-5に基づくうつ症状の評価では、COVID-19発症前は、うつ病の診断を下すための基準を満たさなかったことから、両者ともに、うつ病には該当しないと判断した。しかし、罹患後、いずれも抑うつ状態になった。
基本的方法は、実施例１及び５に準じた。初期投与量はクロミプラミンを1日10mgの経口投与とした。
20代女性は、10mgの投与のまま、その後、いずれの症状も軽快した。50代女性は倦怠感や不眠については改善が認められたが、COVID-19罹患後に表出した不安や焦燥等の症状については服用11週目で若干の改善しか認められなかったため、さらなる改善を目指してクロミプラミンを1日20mgに増量して経過を観察した。その結果、劇的に改善し、その後、完治した。 (Progression of symptoms)
[7th day of taking]
On the seventh day, the dose of clomipramine was increased to 20 mg per day, and fatigue improved significantly two days after the dose increase (2/10 scale). However, fatigue worsened (6/10 scale) on the day after not taking the drug. Currently, the patient is still taking 20 mg, and fatigue has not recurred.
<Example 5: Treatment of COVID-19 sequelae in healthy individuals (2)>
(the purpose)
The efficacy of the drug was examined in patients of a different age group from that in Example 1 who were in a healthy state but contracted COVID-19 and developed sequelae of viral infection.
(Method)
Subject: A woman in her 50s with COVID-19. Vaccination history: Received three doses of the Pfizer COVID-19 vaccine. COVID-19 infection and symptoms: After receiving the third dose of the vaccine, she contracted the virus at work, where COVID-19 was prevalent. She began coughing, but an antigen test at work was negative. After returning home, she developed a fever of around 38 degrees, and a PCR test the next day determined that she was positive.
- Acute symptoms: fever, cough, shortness of breath, fatigue, headache, loss of taste and smell, oxygen saturation ( SpO2 ) decreased to 88%.
・Progression: The patient was diagnosed in early February, and even 10 days after the end of the recuperation period, he still had coughing, shortness of breath, and loss of appetite. He was unable to speak due to his cough, so he was recuperating at home until the end of February. After that, he worked half-days for two weeks, and then returned to full-time work, but his shortness of breath and coughing symptoms continued until around July, and in September he lost consciousness while exerting himself and fell. After being transferred to another hospital in early October, his symptoms at the time of his first visit included fatigue (at rest and while active), coughing, chest tightness, dyspnea, insomnia, cognitive impairment, anxiety, headache, and tinnitus. Dyspnea during exertion is likely to occur when the patient continues to move or talk, and SpO2 can drop to as low as 93%. A chest CT scan to check the condition of the lungs revealed no obvious findings.
It was confirmed using the evaluation method of Example 1 that the symptoms in the subjects of this example were not depressive symptoms.
(result)
(1) Diagnostic results (a) The evaluation of depressive symptoms based on the SCID-5 did not meet the criteria for diagnosing depression, and therefore it was determined that the patient did not have depression.
(b) In the cognitive function evaluation, the subjects' cognitive functions before taking clomipramine were converted and calculated into Z-scores (a value between -1.0 and 1.0, taking into account gender and age, with the general average being used). Verbal fluency was the lowest at -1.30, followed by working memory at -0.96. These results revealed that the subjects' verbal fluency had declined significantly compared to the general average for women in their 50s.
(2) Symptom progression [start of treatment (day 0)]
Clomipramine was administered orally at 10 mg per day and the patient's condition was monitored.
[13th day of taking the drug (2 weeks)]
Although some changes were observed in physical symptoms and cognitive impairment, the dose of clomipramine was increased to 20 mg per day in an attempt to achieve further improvement, and the patient's progress was monitored.
[27th day of taking the drug (4 weeks)]
On a subjective scale of 100, dyspnea on exertion improved dramatically to 20. Similarly, brain fog, cognitive impairment (speed of processing, ability to concentrate), and executive dysfunction improved to 30. Fatigue also improved to 70.
[Day 41 (6 weeks)]
Brain fog, cognitive impairment, and executive dysfunction further improved to 10. A cognitive assessment (BACS) was performed, with verbal fluency improving from -1.03 to -0.47, and information processing speed improving from 0.02 to 0.31.
[56th day of taking the drug (8th week)]
Although the above symptoms were improved, the patient still had no clear feeling about fatigue, and the sleep disorder had not improved. Therefore, the dose of clomipramine was increased to 30 mg per day and the progress was observed.
[69th day of taking the drug (10th week)]
Fatigue was dramatically reduced from 100 at its worst to 20, the feeling of exhaustion disappeared, and the patient was able to continue moving. Insomnia was also improved, and the patient felt better upon waking. There were no further abnormalities in brain fog, cognitive function, or executive dysfunction.
[78th day of taking the drug (11th week)]
All symptoms have improved, and the patient is able to perform work at almost the same level as before COVID-19. Cognitive function assessment (BACS) showed that verbal fluency improved from -1.30 before treatment to -0.16, information processing speed improved from 0.02 before treatment to 0.80, and verbal memory improved significantly from -0.25 before treatment to 1.01.
<Example 6: Treatment of COVID-19 sequelae in healthy individuals (3)>
(Objectives and Methods)
In addition, the efficacy of the drug was examined in female patients in their 20s and 50s who had previously been healthy but had contracted COVID-19 and subsequently developed aftereffects of the viral infection.
According to the SCID-5 evaluation of depressive symptoms, neither patient met the criteria for a diagnosis of depression before developing COVID-19, and therefore neither patient was considered to have depression. However, after contracting COVID-19, both patients became depressed.
The basic method was the same as in Examples 1 and 5. The initial dose of clomipramine was 10 mg per day, administered orally.
The woman in her 20s continued to receive 10 mg of the drug, and all symptoms subsequently improved. The woman in her 50s saw improvements in her fatigue and insomnia, but only slight improvements in symptoms such as anxiety and restlessness that appeared after contracting COVID-19 after 11 weeks of taking the drug. In order to achieve further improvement, she increased her clomipramine dose to 20 mg per day and monitored her progress. As a result, her symptoms improved dramatically, and she was subsequently cured.
＜各実施例の結果から＞
実施例１～６の結果を表１に示す。
実施例１～６のいずれの症例においても、10mg/日～30mg/日という極少量にもかかわらず、クロミプラミンの投与後、短期間で消化器症状、倦怠感、味覚障害、嗅覚障害が軽減した。一方、少量投与のため、副作用は認められていない。クロミプラミンは、ウイルス感染後遺症患者であれば、年代、性別、及びウイルス感染後遺症罹患前の病歴（現病歴）にかかわらず、ウイルス感染後遺症の軽快、寛解、及び治療に有効であることが明らかになった。
From the results of each example
The results of Examples 1 to 6 are shown in Table 1.
In all cases of Examples 1 to 6, despite the extremely low dose of 10 mg/day to 30 mg/day, after administration of clomipramine, digestive symptoms, fatigue, taste disorders, and olfactory disorders were alleviated in a short period of time. Meanwhile, because of the low dose, no side effects were observed. It has been revealed that clomipramine is effective in alleviating, remitigating, and treating viral infection sequelae in patients with viral infection sequelae, regardless of age, sex, and medical history (current medical history) before the onset of viral infection sequelae.
実施例１～６の結果を表１に示す。
The results of Examples 1 to 6 are shown in Table 1.
クロミプラミンは三環系抗うつ薬の一種である。しかし、他の抗うつ薬を服用しているうつ病患者においてもCOVID-19罹患後、又はCOVID-19ワクチン接種後に発症した前記消化器症状、倦怠感、味覚障害、嗅覚障害等の各症状がクロミプラミンの投与により顕著に改善したことから、これらの症状はうつ病ではなく、COVID-19等のウイルス罹患による感染症による後遺症、及びワクチン接種による後遺症（本明細書では、これらをまとめてウイルス感染後遺症と称する）であり、クロミプラミン等の三環系抗うつ薬がウイルス感染後遺症の軽快、寛解、及び治療に有効であることが立証された。
本明細書で引用した全ての刊行物、特許及び特許出願はそのまま引用により本明細書に組み入れられるものとする。 Clomipramine is a type of tricyclic antidepressant. However, even in patients with depression who were taking other antidepressants, the symptoms of the digestive system, fatigue, taste disorder, olfactory disorder, etc., which developed after COVID-19 infection or after COVID-19 vaccination, were significantly improved by administration of clomipramine. This proves that these symptoms are not depression, but sequelae of infectious diseases caused by infection with a virus such as COVID-19, and sequelae of vaccination (collectively referred to as viral infection sequelae in this specification), and that tricyclic antidepressants such as clomipramine are effective in alleviating, remitigating, and treating viral infection sequelae.
All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.
本明細書で引用した全ての刊行物、特許及び特許出願はそのまま引用により本明細書に組み入れられるものとする。 Clomipramine is a type of tricyclic antidepressant. However, even in patients with depression who were taking other antidepressants, the symptoms of the digestive system, fatigue, taste disorder, olfactory disorder, etc., which developed after COVID-19 infection or after COVID-19 vaccination, were significantly improved by administration of clomipramine. This proves that these symptoms are not depression, but sequelae of infectious diseases caused by infection with a virus such as COVID-19, and sequelae of vaccination (collectively referred to as viral infection sequelae in this specification), and that tricyclic antidepressants such as clomipramine are effective in alleviating, remitigating, and treating viral infection sequelae.
All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.
Claims (7)
- 以下の一般式（I）及び／又は一般式（II）で示される三環式化合物又はその塩からなるウイルス感染後遺症抑制剤。
- 前記ウイルス感染後遺症が精神疾患を含まない脳機能障害である、請求項１に記載のウイルス感染後遺症抑制剤。 The agent for suppressing sequelae of viral infection according to claim 1, wherein the sequelae of viral infection are brain dysfunctions not including psychiatric disorders.
- 前記ウイルス感染がワクチン接種を含む、請求項１又は２に記載のウイルス感染後遺症抑制剤。 The agent for suppressing sequelae of a viral infection according to claim 1 or 2, wherein the viral infection includes vaccination.
- 前記ワクチン接種に用いるワクチンがCOVID-19ワクチン、インフルエンザワクチン、又は子宮頸癌ワクチンである、請求項３に記載のウイルス感染後遺症抑制剤。 The agent for suppressing sequelae of viral infection according to claim 3, wherein the vaccine used in the vaccination is a COVID-19 vaccine, an influenza vaccine, or a cervical cancer vaccine.
- ウイルスがSARSコロナウイルス2、インフルエンザウイルス、又はヒトパピローマウイルスである、請求項１又は２に記載のウイルス感染後遺症抑制剤。 The agent for suppressing sequelae of viral infection according to claim 1 or 2, wherein the virus is SARS coronavirus 2, influenza virus, or human papilloma virus.
- 請求項１又は２に記載のウイルス感染後遺症抑制剤を有効成分として１又は２以上含むウイルス感染後遺症抑制組成物。 A composition for suppressing the sequelae of viral infection, comprising one or more of the agents for suppressing the sequelae of viral infection according to claim 1 or 2 as active ingredients.
- 一日の投与単位中に10mg以上40mg以下の前記ウイルス感染後遺症抑制剤を含む、請求項６に記載のウイルス感染後遺症抑制組成物。
7. The composition for suppressing sequelae of viral infection according to claim 6, comprising 10 mg or more and 40 mg or less of said agent for suppressing sequelae of viral infection in a daily dosage unit.
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| WO2022181219A1 (en) * | 2021-02-24 | 2022-09-01 | 国立大学法人九州大学 | Therapeutic drug for novel virus infectious disease |
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| Title |
|---|
| RISHABH KHATRI: "Functional Dyspepsia: A Sequelae After COVID-19.", AMERICAN JOURNAL OF GASTROENTEROLOGY., vol. 116, 1 October 2021 (2021-10-01), pages S938, XP093160174, DOI: 10.14309/01.ajg.0000782280.97089.5c * |
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